top of page
Poster Details
View abstracts and poster details for the 2024 VCP International Conference.
Poster Abstracts - VCP Structure and Function
Below are the poster location and abstracts submitted in the Structure and Function Category.
Presented by Carly Pontifex, PhD candidate, University of Calgary, Canada
The Multisystem Proteinopathy (MSP) phenotype can arise from variants in several genes including HNRNPA2B1, HNRNPA1, MATR3, VCP, SQSTM1, and OPTN. Since impairments in autophagy and stress granule regulation are a common to all MSP genes, we hypothesized that two MSP mutants VCP and SQSTM1 with TIA1 modifier variants will share similarities in their autophagic and stress granule deficits. We studied stress granule dynamics, autophagic flux, stress granule loading into autophagosomes, number of autophagosomes, lysosome volume and lysosome intensity. While VCP and SQSTM1 both had aberrant stress granule dynamics and lysosomal accumulation in response to arsenite stress, they differed in autophagosome accumulation, autophagic flux, and lysosomal localization. We found that VCP has enhanced autophagic flux, while SQSTM1 had impaired autophagic flux. We also ask why TIA1 leads to a distal phenotype, with preliminary findings showing that the TIA1b isoform may be the predominant isoform contributing to pathogenesis with the TIA1b isoform stress granules colocalizing poorly to SQSTM1 while also being more expressed in distal muscle.
Presented by Carly Pontifex, PhD candidate, University of Calgary, Canada
In this review, we examine the functionally diverse AAA-ATPase, valosin-containing protein (VCP/p97), its molecular functions, the mutational landscape of VCP, and the phenotypic manifestation of VCP disease. VCP is crucial to a multitude of cellular functions including protein quality control, ERAD, autophagy, mitophagy, lysophagy, stress granule formation and clearance, DNA replication and mitosis, DNA damage response including nucleotide excision repair, ATM and ATR mediated damage response, homologous repair and non-homologous end joining. VCP variants cause multisystem proteinopathy, and pathology can arise in several tissue types such as skeletal muscle, bone, brain, motor neurons and sensory neurons and possibly cardiac muscle, with the disease course being challenging to predict.
Presented by Chad Altobelli, UCSF
VCP/p97 is a homohexameric AAA-ATPase that is ubiquitously expressed in human cells. VCP acts as a molecular motor to unfold proteins through its central pore, thereby making them available for downstream processing. There are at least 32 proteins, termed adaptors, that bind VCP directly to provide substrate specificity and control subcellular localization. One such adaptor, UBXD1, is structurally unique because it binds both the N- terminal and C-terminal domains of VCP. Biochemical assays indicate that UBXD1 inhibits the basal ATPase activity of VCP with a low nM IC50. To better understand this interaction, we determined a high resolution cyro- EM structure of full length UBXD1 in complex with VCP. The structure reveals that beyond the two predicted contacts, UBXD1 also wraps around the N-domain of VCP using a lariat-like motif and wedges itself between the D1 and D2 domains of VCP. Mutational analysis suggests that while each UBXD1 domain contributes towards VCP inhibition, most inhibition stems from the C-terminal half of the protein that includes a lariat structure anchored to the bottom of VCP. This engagement ultimately results in a shallow split- washer conformation of the hexamer and substantial separation between two protomers bridged by UBXD1. This unique complex may be important for substrate engagement or processing.
Presented by Alex Long, UCSF
VCP/p97 is a AAA+ ATPase that serves critical functions as a segregase in a diverse set of cellular processes. Familial mutations in VCP are associated with multisystem proteinopathies and neurodegeneration. VCP requires a network of more than 30 adapter proteins to modulate activity and engage protein substrates. Many disease mutants increase ATP hydrolysis and potentially alter its adapter interactions and conformational cycle, thus the development of small molecule therapeutics that restore wild type hydrolysis levels are of substantial interest. Our focus is to understand how VCP structural states and ATPase activity are modulated by disease mutations, small molecules, and adapter interactions. We have previously investigated the multi-domain adapter UBXD1, solving the structure of the UBXD1-VCP complex and identifying it as a potent inhibitor of VCP ATPase activity; however, the molecular mechanisms of this inhibition are not well understood. To dissect the contributions of adapter interactions in hydrolysis control, we are studying the small VCP-interacting protein (SVIP), another inhibitory adapter that contains a VIM-helix motif structure similar to what we identify in UBXD1. Here, I present structures of VCP-SVIP complexes and ATPase data of various SVIP mutations that advance understanding of the mechanisms of adapter-mediated VCP inhibition.
*YOUNG INVESTIGATOR AWARD WINNER*
Presented by Eileen Lynch PhD, from the Weihl lab, department of Neurology, Washington University
Valosin-containing protein (VCP) is critical for the maintenance of proteostasis, with roles in endocytosis, autophagy, the proteasome, and many other cellular processes. Mutations in VCP can lead to a spectrum of diseases including frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), and inclusion body myopathy (IBM). Cytoplasmic aggregates of the normally nuclear-localized protein TDP-43 are a characteristic feature of pathology in both the brains of patients with FTD/ALS and the muscles of patients with IBM. TDP-43 is an RNA-binding protein that in certain disease conditions behaves in a prion-like manner, forming insoluble aggregates and inducing other TDP-43 monomers to misfold and aggregate, a process referred to as seeding. Previous work from our lab has demonstrated that VCP inhibition or knockdown facilitates TDP-43 seeding in primary mouse cortical neurons. More recently we have also developed a seeding assay that will be used to determine differences in TDP-43 seeding in WT versus VCP patient iPSC-derived motor neurons. The same WT and VCP patient iPSC lines were differentiated into skeletal myocytes. At baseline, VCP patient myocytes have increased insoluble TDP-43 which further increases with arsenite-induced stress. Additionally, mouse C2C12 differentiated myotubes stressed with arsenite and then treated with a VCP inhibitor during recovery had delayed clearance of insoluble TDP-43. To study TDP-43 aggregation in skeletal muscle in vivo, we developed a transgenic mouse line with doxycycline-inducible cytoplasmic mislocalized human TDP-43 specific to skeletal muscle (HSA-hTDP-43ΔNLS). These mice form abundant sarcoplasmic TDP-43 insoluble aggregates when the transgene expression is activated. When the transgene is turned off, insoluble TDP-43 is cleared from muscle but TDP-43 aggregate seeding persists. When the HSA-hTDP-43ΔNLS mice were crossed with VCPR155H/WT mice, the resulting mice have increased persistence of insoluble TDP-43 but decreased seed generation during recovery. We hypothesize that regular VCP function is involved in the clearance of insoluble TDP-43 aggregates but this process may generate more seeding-competent intermediates initially. Together, these studies support a role for VCP in the seeding and clearance of TDP-43 aggregates in both neurons and muscle, suggesting similar mechanisms between the tissue types that could be targeted therapeutically.
This poster will be presented at the YIA oral session on February 24
Presented by Deirdre Mack, PhD candidate, University of Utah
Cells must maintain a balance between generating, folding, transporting, and degrading proteins in order to maintain proper protein homeostasis, or proteostasis. A central player in the maintenance of mammalian proteostasis is VCP (also known as p97 or Cdc48), a AAA+ ATPase (ATPase associated with diverse cellular activities) that leverages the power of ATP hydrolysis to pull ubiquitinated substrates from a variety of organelles and unfold them before proteasomal degradation. Mutations in VCP can lead to diseases associated with dysregulation of proteostasis; thus, while it is known that VCP is critical to cellular health, much about its mechanism remains unknown. In general, VCP must bind, translocate, and release the unfolded substrate. Each of these steps is dependent on VCP’s interactions with multiple binding partners, yet how these interactions are coordinated has not been fully characterized. Although it is well established that VCP complexes bind and process ubiquitinated substrates, it has also been shown that VCP cannot release these substrates without the help of another binding partner: Otu1. Otu1 is a deubiquitinase (DUB) that interacts with VCP and trims ubiquitin moieties on substrates to allow for efficient unfolding and release. Yet, how this trimming occurs during substrate unfolding remains an open question. To elucidate how VCP is regulated by Otu1 and how Otu1 interacts with polyubiquinated substrate, I aim to determine a high-resolution structure of the VCP-Otu1 complex with polyubiquitinated substrate via cryo-EM and an unfolding assay. In order to capture VCP bound to Otu1 while in the process of deubiquitinating substrate, I have reconstituted active complexes in vitro using purified VCP hexamers, the Otu1 DUB in its wild-type or catalytically inactive form (Otu1C120S), the substrate recruiting heterodimer Ufd1/Npl4, and a fluorescent polyubiquitinated substrate. To determine how Otu1 influences the rate of unfolding activity of VCP I use the same components (Otu1, VCP, UN, and substrate) in a fluorescence based unfolding activity assay. This work will elucidate how polyubiquitinated substrates are deubiquitinated, will construct a more complete understanding of how VCP processes its substrates, and has implications for the development of therapeutics for degenerative diseases associated with failure in protein quality control.
Presented by Dale Martin, PhD, University of Waterloo, Canada
Protein mislocalization is one of the first steps in neurodegeneration, leading to proteostasis deficiencies and cell death, typically linked to protein aggregation. Thus, defining the mechanisms that regulate subcellular protein localization is critical for understanding cell biology and disease progression, as well as for developing effective therapeutics targeted to the earliest stages in disease pathogenesis. The pleiotropic effects combined with the disconnect between genotype and phenotype suggest modifiers may play a role in Multisystem proteinopathy (MSP). We have identified palmitoylation of VCP and one of its co-factors, small VCP-interacting protein (SVIP), as a novel disease modifier in MSP. Palmitoylation involves the reversible addition of the fatty acid palmitate to cysteine residues and promotes membrane binding, protein-protein interactions, and protein stability. Much like phosphorylation, reversibility is highly dynamic making palmitoylation an emerging drug target. Many disease-causing VCP mutations exist and targeting each mutation separately is difficult and costly. Consequently, identifying a common pathway or target affected by more than one VCP mutation, like palmitoylation, could provide a common therapeutic strategy for VCP diseases and, potentially, other neuronal, muscle, and bone diseases. We recently showed that dynamic palmitoylation acts as a novel regulator of VCP and VCP co-factors in MSP and amyotrophic lateral sclerosis. We have identified two novel pathways that specifically alter VCP localization and regulate mutant VCP toxicity: (i) VCP binding to and palmitoylation by palmitoylating enzymes (ii) in conjunction with fatty acylation of VCP co-factor SVIP. We aim to map the inter-relationships of VCP, SVIP, and their palmitoylating enzymes to understand their complex biological role in VCP cell biology and elucidate VCP dysregulation in MSP disease pathogenesis.
Presented by Carly Pontifex, PhD candidate, University of Calgary, Canada
Multisystem Proteinopathy (MSP) genes can be divided into two types, the RNA-binding splicing regulators that are sequestered into stress granules and ubiquitin-binding autophagy regulators. According to Wheeler et al. 2022, RNA-binding splicing regulators that cause MSP such as HNRNPA1 and HNRNPA2B1 are upregulated during myogenic differentiation. We hypothesize that there is a common mechanism that functionally unites these genes and contributes to the pathogenesis of MSP. We used single nuclear RNA sequencing from frozen muscle biopsies derived from two control patients and four myopathy patients, including a sporadic inclusion body myositis patient and a SQSTM1 MSP patient. When Ingenuity Pathway Analysis was used to analyze the top markers of pre-committed myoblast clusters, results suggested impairments in myogenic differentiation. Patient-derived mt-VCP and mt-SQSTM1 fibroblasts were converted to myoblasts using lentiviral MYOD1 transduction followed by staining with late-stage differentiation marker desmin. VCP and SQSTM1 mutants exhibit impaired myogenic differentiation compared to controls. These results suggest that the pathogenesis of inclusion body myopathy in MSP may be driven not only by accelerated atrophy of myofibers, but also by impaired maturation of myonuclei.
Presented by Maxwell Tucker, graduate student at UCSF.
VCP/p97 is a AAA+ segregase that unfolds and disassembles ubiquitinated macromolecular targets via hydrolysis-driven substrate translocation through a central pore. Mutations in VCP are associated with several diseases, including frontotemporal dementia and ALS. One hallmark of these disease states is the disruption of lysosomal regulation. Intriguingly, VCP and several cofactors have been directly linked to lysosomal regulation through the lysophagy pathway, in which damaged lysosomes are degraded through autophagy. While the necessity of VCP complexes in lysosomal regulation is well established, the precise functional role remains unclear. In this work, we are using in situ cryo-electron tomography (cryo-ET) to study the localization of VCP within the ultrastructure of damaged lysosomes. This technique allows for nanometer-resolution within the native context of a cell. We have developed a pipeline for initiating lysosome damage and targeting VCP-associated damaged lysosomes using correlative fluorescence microscopy and FIB-milling. These samples are used for high resolution cryo-ET collection and 3D structural characterization of VCP-like densities in proximity to damaged membranes. Placing VCP in the cellular ultrastructure of a damaged lysosome will shed new light on its function in this critical pathway.
Presented by Johannes Van Den Boom, PhD, University of Duisburg-Essen, De
The AAA+ ATPase p97 is a major protein unfolding machine with hundreds of clients in diverse cellular pathways that are critical for cell homeostasis, proliferation and signaling. Client proteins are recruited to p97 by at least two types of alternative adapters. The Ufd1-Npl4 adapter along with accessory adapters targets ubiquitylated clients in the majority of pathways and uses ubiquitin as a universal unfolding tag. In contrast, the family of SEP-domain adapters such as p37 can target clients directly to p97 in a ubiquitin-independent manner. We now present a cryo-EM structure of p97 and p37 in the act of disassembling a protein phosphatase-1 (PP1) complex that together with biochemical evidence suggests a hold-and-extract mechanism for PP1 complex disassembly. PP1 is held in an inactive complex with its binding partners SDS22 and inhibitor-3 (I3) during PP1 biogenesis and formation of active PP1 holoenzymes with substrate specifiers requires disassembly of the SDS22-PP1-I3 complex by p97. During the disassembly reaction, SDS22 with PP1 is firmly locked directly onto one of the N-domains of p97. The p37 adapter is located underneath and bridges two N-domains with multivalent interactions to the PP1 complex suggesting that p37 helps position PP1-SDS22 complex. I3 is inserted into the central pore of p97 in active staircase conformation while I3 is still attached to PP1 indicating that I3 is stripped off PP1 by threading I3 through the pore. Our data uncover how p97 releases PP1 from its inhibitory partners for activation and demonstrate a remarkable plasticity in substrate threading by p97.
Presented by Yihong Ye, PhD, Senior Investigator, NIH, NIDDK, Laboratory of Molecular Biology.
In eukaryotic cells, a protein translation surveillance system named ribosome-associated Quality Control (RQC) degrades partially translated products, resolving translation stress caused by prolonged ribosome stalling. Central players of this process include ribosome-associated ubiquitin ligases, which collaborate with the AAA ATPase p97 to target ubiquitinated RQC substrates for proteasomal degradation. While this pathway has been well characterized for ribosomes stalled on mRNAs encoding soluble proteins, little is known about how cells handle ribosomes stalled while making a membrane or secretory proteins at the endoplasmic reticulum (ER), a key protein biogenesis hub of eukaryotic cells. Using two distinct mammalian ER RQC reporters, we performed genome-wide CRISPR knockout screens, which identified players involved in ER RQC processes. Our study delineates two parallel quality control systems: One shuttles a defective RQC substrate from the ER to the lysosome in a p97-independent mechanism, while the other targets an ER RQC substrate to the proteasome via the p97-UFD1-NPL4 complex. Interestingly, both processes require post-translational modification of the large ribosomal subunit RPL26 with a small ubiquitin-like protein named UFM1. While both RQC substrates are released into the ER lumen for transporting to the Golgi, an ER RQC substrate translated from a mRNA with no stop codon is retrieved back to the ER, from where it is retrotranslocated into the cytosol by p97 and degraded by the proteasome. Our study has revealed an unexpected role for p97 in maintaining ER homeostasis by safeguarding protein translocation at the ER membrane.
Speaker at session#1, Structural VCP &Biochemistry, February 23.
Presented by Isabelle Rouiller, PhD, the University of Melbourne, Australia
Single-particle cryo-electron microscopy (cryo-EM) has proven effective in determining the structure of VCP in different conformations including those linked to mutants associated with multisystem proteinopathy development, as well as its interactions with substrates and co-factors [1]. However, most published cryo-EM maps exhibit heterogeneous resolution, leading to ambiguities and unresolved segments within the VCP, VCP/co-factors and VCP/substrate protein complexes. This artifact stems from the average of many images of the complexes needed to retrieve the signal from noisy cryo-EM data, resulting in reduced definition and, at times, elimination of density from flexible regions of the protein. Flexible regions of VCP, such as the indispensable N-domains [2], play pivotal roles in co-factor and substrate recruitment, and their dynamic properties are influenced by disease-causing mutations [3,4]. Regrettably, these regions of critical functional importance often suffer from diminished resolution in cryo-EM studies. Our recently developed image analysis method relies on a 3D-to-2D flexible fitting strategy, enabling the modification of an atomic structure through Molecular Dynamics (MD) simulations while utilizing the cryo-EM images as constraints [5]. This innovative approach facilitated a comprehensive exploration of the conformational dynamics within VCP as captured in the cryo-EM data. Specifically, it enabled the characterization of the entire spectrum of conformations adopted by VCP's N-domains [6] and enabled the detection of novel particle conformations within our cryo-EM dataset. Leveraging this methodology, we conducted a comparative analysis between the dynamic properties of wild-type VCP and VCP bearing the R155P mutation. Additionally, our findings were corroborated through Cross-Linking mass spectrometry (XL-MS), Hydrogen Deuterium Exchange mass spectrometry (HDX-MS) and NMR spectroscopy. Collectively, our methodology enables the analysis of VCP’s diverse conformational landscape embraced by VCP, providing crucial insights for drug discovery. A comprehensive structural characterization of VCP's conformations will aid in identifying novel active sites, designing higher-affinity ligands, and targeting disease-associated conformations or modulating protein function. [1] Valimehr et al. AAA ATPase multifunctional protein, VCP/p97; an important therapeutic target. Biomolecules. 2023 Apr 24;13(5):737. doi: 10.3390/biom13050737. [2] Rouiller, I., et al., Conformational changes of the multifunction p97 AAA ATPase during its ATPase cycle. Nat Struct Biol, 2002. 9(12): p. 950-7. [3] Mountassif et al., Cryo-EM of the pathogenic VCP variant R155P reveals long-range conformational changes in the D2 ATPase ring. Biochem Biophys Res Commun, 2015. [4] Halawani et al., Hereditary inclusion body myopathy-linked p97/VCP mutations in the NH2 domain and the D1 ring modulate p97/VCP ATPase activity and D2 ring conformation. Mol Cell Biol, 2009. 29(16): p. 4484-94. [5] Vuillemot et al., MDSPACE: Extracting Continuous Conformational Landscapes from Cryo-EM Single Particle Datasets Using 3D-to-2D Flexible Fitting based on Molecular Dynamics Simulation. J Mol Biol, 2023: p. 167951. [6] Valimehr et al., Analysis of the conformational landscape of the N-domains of the AAA ATPase: disentangling continuous conformational variability of partially symmetrical complexes. Manuscript under review.
Presented by Mengcheng Wu, PhD Student, Caltech
p97 is an abundant protein that participates in multiple cellular functions, including Endoplasmic-reticulum-associated protein degradation(ERAD), DNA damage response, and autophagy. Binding with the correct cofactor(s) is crucial for p97's involvement in these pathways. Numerous p97 mutations can cause the neurodegenerative disease multisystem proteinopathy type 1(MSP1), characterized by symptoms such as muscle and/or bone weakness. Although it is suspected some cellular functions are impaired due to incorrect cofactor binding, the specific pathogenesis mechanism at the cellular level remains unclear. To address this gap, we developed three p97 mutant cell lines(R155H, K164Q, F267del) on HEK293 cells to express p97 mutants while knocking down endogenous p97. Our primary objectives are to analyze the p97 interactome in the three mutant cell lines using liquid chromatography–mass spectrometry(LC-MS). This analysis aims to determine (1) if there is a common pathogenesis mechanism and (2) to identify the specific mechanism(s) potentially causing the neurodegenerative disease MSP-1.
Presented by Wenyan Li, PhD, University of Utah
The linear chains of amino acids are synthesized on ribosomes, then it must fold into unique three-dimensional structures to obtain their biological functions. The product of truncated polypeptides by stalling of ribosomes during protein synthesis must be eliminated. Ribosome Quality control Complex (RQC) sense the 60S subunit obstructing with the nascent chain then mediates nascent chain degradation to maintain cellular protein homeostasis. In this work, we describe the cryo–electron microscopy structure of the whole RQC complex. Through analyzing the structure, we elucidate the mechanism of how p97/Cdc48 functions in this process.
Poster Abstracts - VCP Therapeutic Approaches and Translational Research
Below are the poster location and abstracts submitted in the Therapeutic Approaches and Translational Research Category.
Presented by Alyaa Shmara, PhD, UCI
Background and Rationale: Mutations in the Valosin-Containing Protein (VCP) gene cause multisystem proteinopathy type 1 (MSP1) associated with inclusion body myopathy, Paget disease of bone, frontotemporal dementia, and ALS. One of the limitations in studying VCP-associated disease has been the unavailability of patient tissue samples due to difficulty of their location (brain, spinal cord, bone, and muscle). Thus, the generation of myoblasts and neurons from disease-specific induced pluripotent stem cells (iPSC) offers an abundant and renewable supply of cells to investigate potential treatments in vitro. We have previously studied the cellular consequences of VCP mutations in patient cell lines and found TDP-43 and disrupted autophagic pathology in addition to changes in the mitochondrial dynamics and bioenergetics. However, several challenges remain in the generation and maintenance of iPSC derived myoblasts, thus hampering translational ability.
Methods: Using a robust and reproducible protocol, we differentiated and characterized skeletal muscle progenitor cells (SMPC) derived from disease-specific iPSCs from patients with inclusion body myopathy and Paget disease, identified with the most common R155H variant. To validate our newly differentiated myoblasts as a disease model, we used a small molecule (SBT-272) which is found to improve TDP-43 pathology in ALS upper motor neurons by modulating mitochondrial integrity and function. SBT-272 stabilizes cardiolipin, a phospholipid found in inner mitochondrial membrane.
Results: Our characterization studies of iPSC derived myoblasts manifested the typical pathology of VCP MSP1. Protein analysis with western blot and immunocytochemistry showed upregulation of TDP-43, ubiquitin, and autophagy markers p62 and LC3BII when compared to control SMPCs. The R155H SMPCs were treated daily with 500 nM SBT-272 for 3 days and the effect on TDP-43 and autophagy markers was analyzed. Upon treatment with SBT-272, we noticed downregulation of autophagy, ubiquitin, and TDP-43.
Conclusion: SMPC derived from MSP1 patients’ iPSCs, identified with the most common R155H variant can be used as a valid disease model to investigate disease pathogenesis and test potential therapeutics.
Presented by Sukanya Banerjee, PhD, University of Pittsburgh
Insoluble tau deposits are observed in neurons and microglia in various neurodegenerative diseases including Alzheimer's disease, frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) and progressive supranuclear palsy. Loss of function mutations in PTEN-induced kinase 1 (PINK1) are associated with recessive Parkinson’s disease (PD) and early-onset PD with dementia. Loss of PINK1 causes simplification of dendritic architecture, decreased spine density and maturation. PINK1 interacts with VCP and promotes phosphorylation of the VCP co-factor NSFL1C/p47. Elevation of the p47D phosphomimic can mimic the effects of human PINK1 overexpression and rescue dendrite simplicity in Pink1-/- mouse neurons. As transcriptional loss of wild type PINK1 is also observed in Alzheimer's disease, I hypothesized that PINK1 and VCP may cooperate to rescue tau pathology. To explore this, mouse primary cortical neurons were cultured and transfected at 7d in-vitro (DIV7) with VGFP and either 2N4RWT tau or pcDNA vector. Neurons were fixed and immunofluorescence was performed 7d after transfection (DIV14) to study neuronal morphology. Sholl analysis showed that 2N4RWT tau caused dendritic simplification which was rescued by elevation of PINK1 with a partial rescue when VCP was overexpressed. From this study, we conclude that 2N4RWT tau caused significant dendritic simplification, which was significantly improved after elevation of either PINK1 or VCP. Ongoing studies will define the possible role of various VCP cofactors, determine if changes in insoluble tau are present, and investigate whether PINK1 and VCP protect through independent or shared mechanisms.
Presented by Sushobhna Batra, Ph.D., UT Southwestern
Tau aggregation and propagation underlie neurodegenerative tauopathies, whereby an aggregate released from one cell gains entry to an adjacent or connected cell and serves as a template for its own replication in the cytoplasm. This process is termed seeding. While in vitro seeding reactions can take days, cytoplasmic seeding occurs within hours. The cellular factors that control seed amplification, however, remain unknown. To address this, we used proximity labeling and fused split-APEX2 to the repeat domain of tau to reconstitute peroxidase activity upon seeded intracellular tau aggregation. We identified valosin-containing protein (VCP/p97) as the most enriched hit of the tau aggregation-initiation proteome. To study the effects of VCP on tau seeding, we utilized HEK293T tau biosensor cells, a cellular model for tau aggregation. Knockdown of VCP reduced tau seeding. Distinct chemical inhibitors of VCP had opposing effects on aggregation: ML-240 increased whereas NMS-873 decreased seeding efficiency. This pharmacological effect was observed only when VCP was inhibited in the initial 8h of the seeding process. We further screened VCP co-factors in biosensor cells by genetic knockout or knockdown. Reduction of ATXN3, NSFL1C, UBE4B, NGLY1, and OTUB1 decreased tau seeding. Knockdown of NPLOC4 also inhibited seeding while also increasing soluble tau levels. Reduction of FAF2, however, increased tau seeding. Thus, VCP determines tau seed replication efficiency via its distinct cofactors, consistent with a dedicated cytoplasmic machinery that directs seeds towards dissolution or amplification.
Presented by Ziwen Jiang, PhD, Department of Pharmaceutical Chemistry UCSF
Protein–protein interactions (PPIs) form complex networks to drive cellular signaling and cellular functions. Precise modulation of a target PPI helps explain the role of the PPI in cellular events and possesses therapeutic potential. For example, valosin-containing protein (VCP/p97) is a hub protein that interacts with more than 30 adaptor proteins involved in various cellular functions. However, the role of each p97 PPI during the relevant cellular event is underexplored. The development of small-molecule PPI modulators remains challenging due to a lack of grooves and pockets in the relatively large PPI interface and the fact that a common binding groove in p97 binds to multiple adaptors. Here, we report an antibody fragment-based modulator for the PPI between p97 and its adaptor protein NSFL1C (p47). We engineered these antibody modulators by phage display against the p97-interacting domain of p47 and minimizing binding to other p97 adaptors. The selected antibody fragment modulators specifically disrupt the intracellular p97/p47 interaction. The potential of this antibody platform to develop PPI inhibitors in therapeutic applications was demonstrated through the inhibition of Golgi reassembly, which requires the p97/p47 interaction. This study presents a unique approach to modulate specific intracellular PPIs using engineered antibody fragments, demonstrating a method to dissect the function of a PPI within a convoluted PPI network.
Presented by Pallabi Pal, PhD, UCI
Valosin-containing protein (VCP) disease is an autosomal dominant disease caused by gain-of function pathogenic variants in the VCP gene. The disease is associated with inclusion body myopathy, with early-onset Paget's disease of the bones, frontotemporal dementia and familial amyotrophic lateral sclerosis, also known as multisystem proteinopathy 1 (MSP1). We hypothesize that regulating VCP hyperactivity to normal levels can reduce the disease pathology. We propose this could be achieved through the reduction of expression in VCP with the use of antisense oligonucleotides (ASOs). In this study, we utilized the transgenic mouse model of VCP disease which overexpresses the humanized VCP gene with the severe A232E mutation. After establishing the validity of the mouse model, we screened ASOs specifically targeting the human VCP gene in the mice harboring wildtype VCP transgene weekly for 8 weeks. At the end-point toxicity analysis, ASO2 demonstrated tolerability in mice. ASO2 showed over 50% knockdown of VCP at the mRNA level and a similar knockdown effect at the protein level. Thereafter, we treated the VCP A232E mice with ASO2 starting from 6 months of age for 3 months and performed monthly motor tests. Interestingly, ASO2 treatment in VCP A232E mice showed significant improvements in the inverted screen compared to mice treated with control ASO. We also found significant reduction in VCP at the protein level upon treatment with ASO2 as compared to control ASO. We then assessed the effect of ASO2 in the patient (R155H) iPSC derived skeletal muscle progenitor cells (SMPCs). ASO2 was well tolerated up to 1200 nM concentration and significantly reduced mRNA and protein expression in cells. These results suggest that knockdown of the mutant VCP allele early in asymptomatic mice and in SMPCs could be beneficial in preventing progression of the myopathy, and holds promise for treatment of clinical features of MSP1 in patients.
Presented by Marius Ueffing, PhD, Director of Tübingen’s Institute for Ophthalmic Research
This poster covers basic and translational research in the field of VCP function with respect to its role in neuronal and neurosensory tissue. The end goal is to understand the cause of retinal diseases, focusing on hereditary retinal degeneration as well as on AMD, and on uncovering molecular mechanisms of retinal disease, identifying disease drivers and biomarkers towards the development of new precision medicine approaches based on the mechanistic and holistic understanding of cellular communication networks.
Presented by Daniela Tamayo, University of Utah
The Valosin-Containing Protein (VCP) is a highly abundant and essential ATPase enzyme that plays a central role in protein homeostasis by unfolding proteins across several cellular pathways. The dysregulation of VCP through mutations or expression levels is associated with several diseases, such as VCP-associated multisystem proteinopathy and many cancers. Multiple efforts to target VCP for disease treatment have been reported, including the development of small molecule inhibitors that impair its ATPase activity. Here, we present a novel compound that directly inhibits VCP. The elucidated structure rationalizes the mode of inhibition and expands the repertoire of VCP inhibitor compounds.
Presented by Sana Ahmed, University British Columbia, Ca
Valosin-Containing Protein (VCP or p97) plays key roles in cellular pathways via its complex interactome and is implicated in cancer due to overexpression and cofactor alterations. Our research utilizes in-cell crosslinking to enrich transient VCP-cofactor complexes, with the aim of uncovering structural insights with potential applications in rational drug design.
Presented by Jocelyn Wood, LSU.
Mutations in Valosin containing protein (VCP) have been implicated in numerous pathologies, including cancer, amyotrophic lateral sclerosis (ALS), and multisystem proteinopathy-1 (MSP-1). We previously generated and characterized nine Drosophila disease models based on mutations in the human VCP gene that result in MSP-1. We observed a wide range of disease pathologies in the mutants, which mirror the stochastic phenotypes observed in human patients with differing mutations. Thus, our models provide a versatile tool for future MSP-1 studies, and we are now using these models as a platform to test potential strategies that can reverse disease phenotypes. We have discovered that small VCP interacting protein (SVIP), a co-factor of VCP, is capable of translocating VCP in the muscle from the nuclei to the lysosomes. Translocation of VCP results in a more robust tubular lysosomal network, which results in improved health and lifespan of wildtype flies. Moreover, SVIP overexpression in the muscles improves late-age mobility and extends lifespan of two MSP-1 mutant models: R152H and R152C (R155H/C in humans). However, the beneficial effects of SVIP overexpression are mutation dependent. For example, overexpression of SVIP does not improve pathology in the P134L mutant model. This is likely because the P134L mutation significantly abrogates VCP-SVIP interaction; thus, increasing SVIP expression cannot promote relocalization of mutant VCPP134L to lysosomes. Taken together, our results highlight SVIP as a promising candidate for patients harboring the R155H/C mutations and also underscore the importance of considering each specific patient mutation when designing potential treatment strategies. We are now conducting further studies to understand the differences between the various VCP disease mutations and how they affect VCP interaction with its co-factors.
Poster Abstracts - VCP Clinical Research
Below are the poster location and abstracts submitted in the Clinical Research Category.
Presented by Madeline Kuan, UCI
Inclusion Body Myopathy Associated with Paget’s disease of Bone and frontotemporal dementia (Multisystem proteinopathy MSP type 1) is an autosomal dominant adult-onset disorder associated with mutations in the valosin-containing (VCP) gene. Muscle weakness is noted in the proximal limb girdle muscular group and results in early demise due to respiratory failure. Limited information is available regarding the impact of this disease on health related quality of life in individuals with VCP MSP1. This study aims to describe health related quality of life surveys in 93 individuals with known VCP mutations, in affected (n=83), versus non-symptomatic carriers of VCP mutations (n=10), and their first degree unaffected relatives (n=26). We used the Inclusion Body Myositis Functional Rating Scale (IBMFRS), and the VCP Quality of Life Questionnaire (VCP QoL). The IBMFRS is a specific tool that can reliably assess an individual’s functional impairment in relation to their degree of severity. The VCP Quality of Life Questionnaire is a 78-item survey composed of the SF-36, the Behavioral Risk Factor Surveillance System, and specific questions pertaining to IBM functional ability. The Physical Health score is composed of subscales that assess physical functioning, role limitations due to physical health, bodily pain, and general health. The Mental Health score is composed of subscales that assess vitality, social functioning, role limitations due to emotional problems, and mental well-being. Results showed that affected individuals had significantly lower IBMFRS scores and quality of life physical functional ability compared to asymptomatic carriers and first degree relatives (p<0.01) (Table 1). The VCP Quality of Life Questionnaire in affected and unaffected individuals displayed significantly lower scores for the physical domain (p<0.01) in the affected group. There were no statistical differences in the mental health domain (p = 0.45). Severity of functional impairment was correlated with overall quality of life (r=0.75), and with physical and mental health (r=0.85 and r=0.13 respectively). This study provides novel information regarding health related quality of life surveys in monitoring progression of the disease in individuals with VCP disease. This survey could be helpful in studying the response to novel treatments in this group of patients.
Presented by Shruthi Balasubramaiyan, University of Pittsburgh
Valosin-containing protein (VCP/p97) is a type II AAA+ ATPase that is ubiquitously expressed in all tissues in multicellular organisms. VCP interacts with various co-factors to regulate multiple cellular processes including chromatin remodeling, Golgi apparatus dynamics, ubiquitin-dependent protein degradation, and autophagy. Mutations in VCP cause progressive autosomal dominant adult-onset multisystem proteinopathies, such as familial amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), cardiomyopathy, and inclusion body myopathy with Paget’s disease of the bone and frontotemporal dementia (IBMPFD). A novel mutation in VCP (T262A) was identified in a familial FTD cohort in Pennsylvania. Multiple affected family members had nuclear aggregates of TAR-DNA binding protein-43(TDP-43) in the brain, characteristic of FTLD-TDP type-IV, which is a sub-type of FTD. In this study, we aim to characterize this mutation and describe how it affects VCP protein function. We found that the T262A mutant pulled down UFDL1 and p47 to a greater extent than the wild type, suggesting increased binding affinities. We found that this mutation shows minimal effects on ER-associated protein degradation (ERAD) using a model ERAD substrate, with significant effects on autophagy. We obtained patient fibroblasts during autopsy and reprogrammed them into induced pluripotent stem cells (iPSCs). We are in the process of using prime editing to create isogenic cell lines expressing the mutant and wild-type VCP protein. Ongoing and future experiments will involve optimizing model systems to study the nuclear and cytoplasmic aggregation of neuronal TDP-43 and using these iPSC lines to better understand the role of VCP mutation in regulating mechanisms of neurodegeneration and neuroprotection.
Presented by Rod Carlo Columbres, UCI
MSP1 disease is a rare genetic disorder caused by mutations in the Valosin-Containing Protein (VCP) gene with clinical features of inclusion body myopathy (IBM), frontotemporal dementia (FTD), and Paget's disease of bone (PDB). We performed bone scan imaging in twelve patients (6 females, 6 males) with confirmed VCP gene mutation six (50%) of which has myopathy alone, four (33%) with both PDB and myopathy, and two (15%) were presymptomatic carriers. We aim to characterize the PDB in diagnosed individuals, and potentially identify PDB in the myopathy and presymptomatic groups. Interestingly, two patients with previously undiagnosed PDB had positive diagnostic findings from bone scan and subsequent radiograph imaging. Among the individuals with PDB, increased radiotracer uptake of the affected bones were of typical distribution as seen in conventional PDB and those reported in other MSP1 cohorts which are the thoracic spine and ribs (75%), pelvis (75%), shoulder (75%) and calvarium (15%). Overall, we show that technetium-99m bone scans done at regular intervals are a sensitive screening tool in patients with MSP1 associated VCP variants at risk for PDB, and diagnostic confirmation should be correlated with clinical history, biochemical analysis, and skeletal radiographs, to enable early treatment and prevention of complications.
Presented by Merwa Hamid, UCI
Objective: The purpose of this study is to utilize the Cure VCP Disease patient registry hosted by the Coordination of Rare Diseases at Sanford (CoRDS) as a tool for monitoring the quality of life (QOL) in patients with VCP disease over a period of time ranging from one to three years. Methods: Seventy-nine participants [males (n=35, 44.3%), females (n=39, 49.4%), enrolled in the Cure VCP Disease patient registry and answered demographic, VCP variant type, patient reported outcome measures (PROMs), and quality of life (QOL) questionnaires over the course of one to three-years. We investigated the progression of QOL, cognitive function, lower extremity function, and upper extremity function by utilizing the 5-point Likert scale, and reviewed correlations between these factors. Furthermore, we analyzed the participants’ reported pain severity levels on a scale from 0 to 10. We assessed the correlation between the individual’s age and sex with the overall rate of deterioration of cognitive function, mobility, and pain using linear regression. We also conducted a genotype-phenotype comparison by observing the correlation between the variant groups, including incidence and onset of the various manifestations. Results: Among the 79 participants, 66 participants were symptomatic (nine were presymptomatic, and four did not provide sufficient information on their status) with myopathy being the most prevalent phenotype affecting 84% of the symptomatic participants. Paget’s disease of bone was reported in 43.4%, dementia was noted in 12.9%, ALS in 4.8%, and Parkinson’s in 1.6%. The overall age spectrum upon enrollment ranged between 21-77 years, and the mean age was 52.3 years. The mean age of diagnosis was 48.9 years and the mean age of onset of symptoms was 42.2 years. Participants revealed a significant decline in total raw score in lower and upper extremities function, in addition to cognitive function with advancing age. Males displayed a slightly more rapid progression in lower extremity function than females [slope = -0.52 (1.3% decrease/yr) versus -0.41 (1.0% decrease/year), respectively, p<0.01]. Females, on the other hand, exhibited exhibited a more rapid decline of cognitive function than males (-0.18, versus -0.06 respectively, p<0.01). Males reported more pain with the progression of the disease (slope = 0.08 versus -0.03, p<0.01) with advancing age. The highest correlations were discovered between general overall health and lower extremity function (0.63), upper extremity function , fatigue, and the ability to perform vigorous activities (0.46 respectively). Individuals report an overall decline of 1.2% in lower extremity function and 0.95% decrease in upper extremity function per year of age. The c. 464G>A, p.R155H VCP variant was the most prevalent and there were no genotype-phenotype correlations. Conclusion: The VCP CoRDS Registry was found to be a valuable tool for monitoring the quality of life in patients with VCP disease. Individuals had an overall decline of 1.2% in lower extremity function and 0.95% decrease in upper extremity function per year of age. Interestingly, declines in cognitive function and mobility were greater in women. Men reported a greater increase in pain as the disease progressed. There were no apparent genotype-phenotype correlations. Studies are ongoing for monitoring patients with VCP disease over an extended period of time. This will enable us to better understand these survey tools and factors such as the VCP genotype, age of diagnosis, including other comorbidities that contribute to the progression of the quality of life symptoms.
Presented by Megan Iammarino, DPT, Nationwide Children’s Hospital, Ohio
Introduction: As a growing number of experimental treatments move toward clinical trial in rare disease populations, The Federal Drug Administration (FDA) has placed increasing emphasis on the importance of documenting a patient’s perception of their disease and the relationship of change with treatment. Currently, there are no disease-specific patient-reported outcome measures (PROs) for individuals with valosin-containing protein multisystem proteinopathy (MSP1) and therefore selection for use in a clinical trial is limited to others that fit within the domains of interest of the disease. The heterogeneity of disease presentation and progression in individuals with MSP1, further highlights the difficulty of identifying a single PRO for use in this population and the importance of exploring this area from a clinical trial readiness perspective. Objective: To determine the responsiveness to change in a selection of PRO in relationship to assessments of motor function, over 2 years; and to compare this change to that of functional outcomes. Methods: In this prospective, two-year natural history study subjects completed a selection of PROs, as well as motor function testing at baseline, 12, and 24 months. The PROs related to motor function included the PROMIS Upper Extremity (UE), Mobility, and Global Health scales; Rasch Overall ALS Disability Scale (ROADS); IBM Functional Rating Scale (IBMFRS); and Patient Global Impression of Change Scale. Results: Nineteen subjects (age 28-66 years) with genetically-confirmed MSP1 have completed all visits, with an additional four subjects having completed at least 12 months. Previously reported in this cohort, statistically significant changes in motor function testing were identified at both 12-month and 24-month time points. At 24-months, percent change in PROMIS Mobility and ROADS were significantly correlated to percent change in performance on mobility motor function assessments (Spearman’s rho=0.64 and 0.56 with p-value<0.01 and 0.05, respectively). The IBMFRS and PROMIS UE were not sensitive to change over time in this cohort. Further analysis will include establishing a minimal clinically important difference (MCID) anchored to patient and clinician global impression of change. Data collection is ongoing and updated analysis to be presented. Conclusions: Our study identified available PROs that demonstrate change consistent to change in motor performance over 24 months in this cohort. Inclusion of the patient perspective is key to successful interpretation of this and future trials in MSP1. Evaluation of the psychometric construction and properties of these scales, with potential future adaptation to optimize meaningfulness and reliability in MSP1, is ongoing.
Presented by Virginia Kimonis, Professor, Division of Genetics and Genomic Medicine Dept. of Pediatrics, Neurology and Pathology University of California, Irvine
Valosin-containing protein (VCP) disease is an autosomal dominant multisystem proteinopathy associated with hereditary inclusion body myopathy, Paget disease of bone, and frontotemporal dementia. Myopathy frequently results in respiratory muscle weakness, leading to early mortality due to respiratory failure. We investigated the effects of a remotely administered inspiratory muscle training program in individuals with VCP disease. Nine adults with VCP mutation-positive familial myopathy without evidence of dementia were recruited for a 40-week remotely administered study. Baseline performance was established during the first 8 weeks, followed by 32 weeks of inspiratory muscle training. The primary outcome was maximum inspiratory pressure (MIP). The secondary and exploratory endpoints included spirometry, grip strength, Inclusion Body Myopathy Functional Rating Scale (IBMFRS), Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS), timed up and go, and six-minute walk test (6MWT). During the treatment phase, MIP increased significantly by a weekly mean of 0.392 cm. H2O (p=0.023). In contrast, grip strength and ALSFRS significantly decreased by 0.088 lbs. (p=0.031) and 0.043 points (p=0.004) per week, respectively, as expected from the natural progression of this progressive disease. A remotely administered inspiratory muscle training program is therefore feasible, safe, and well-tolerated in individuals with VCP disease and results in improved inspiratory muscle strength.
Presented by Leepakshi Johar, Western University
Inclusion body myopathy (IBM) associated with Paget disease of the bone (PDB) and frontotemporal dementia (FTD) or Inclusion Body associated with Paget disease of the bone and frontotemporal dementia (IBMPFD), or Multisystem Proteinopathy (MSP1) is an autosomal dominant degenerative disorder caused by mutations in the valosin-containing protein (VCP) gene. We aim to establish a detailed clinical phenotype of VCP disease amongst 112 (90 affected individuals, 12 presymptomatic gene carriers) individuals versus 37 unaffected first-degree relatives to establish useful biomarkers for VCP myopathy and identify the most meaningful tests for monitoring disease progression. Comprehensive studies included the Inclusion Body Myositis Functional Rating Scale (IBMFRS) and fatigue severity scale (FSS) questionnaires, strength measurements using the Manual Muscle Test with Medical Research Council (MRC) scales, hand-held dynamometry using the microFET and Biodex dynamometers, 6 minute walk test (6MWT), pulmonary function studies, and genotype-phenotype correlations. All muscle groups, except the wrists, tested with the microFET dynamometry indicated a significant difference between affected and unaffected individuals. The mean MRC whole body total score for the affected individuals was 105.17 compared to the score in carriers (125.83), and unaffected individuals (130) out of a maximum score of 130. Significant differences were found of the shoulder abduction and hip flexion. Interestingly, the mean grip strength values using the Jamar dynamometer did not indicate significant differences between the three groups. These studies indicate that affected individuals have proximal muscle weakness, however, the distal muscle groups strength is retained. As a result of our studies, we found correlations between the IBMFRS and various tests of muscle strength. There were strong significant positive correlations between IBMFRS and MRC (r=0.793, p<0.01), between IBMFRS and 6MWT (r=0.734, p<0.01) and a significant, yet low, negative correlation (r=-0.477, p=0.008) between IBMFRS and FSS. These results indicate that IBMFRS can be used for assessing motor function in patients with VCP disease and can be used to easily monitor the progression of motor involvement in VCP disease. Pulmonary function tests were lower on average in affected individuals suggesting a compromise of the lung function due to myopathic involvement of the diaphragm and other accessory muscles of respiration. On reviewing all the parameters in presymptomatic carriers, we found that their scores from tests such as the FSS and 6MWT indicate that they are beginning to manifest symptoms of the myopathy. Based on the MRC scale results, the presymptomatic carriers showed muscle weakness in their shoulders and hips. This study represents a comprehensive evaluation of individuals with VCP disease to date and provides a useful guide for evaluating and possible monitoring of muscle weakness and pulmonary function progression in this unique cohort of individuals.
Presented by Marianela Schiava, MD, John Walton Muscular Dystrophy Centre, Newcastle, UK
Describe the most frequent muscle biopsy findings in an international cohort of patients with VCP and explore their association clinical phenotypes, genotypes and disease progression.
This poster is presented, among other data, as an oral presentation at session#5, Clinical Aspects-Genotype/phenotype, on February 24.
Presented by Lan Weiss, MD. PhD, UCI
Genetically modified adeno-associated virus (AAV)-mediated gene therapies are increasingly common for use in clinical trials; a few of them have been approved for patient treatments by the Food and Drug Administration. Pathogenic variants in Valosin Containing Protein (VCP) gene cause a unique autosomal dominant disease characterized by inclusion body myopathy, Paget disease of bone and frontotemporal dementia (also known as multisystem proteinopathy (MSP)). VCP pathogenic variants lead to hyperactive enzymatic activity, suggesting a gain-of-function. To ameliorate the gain-of-toxicity of VCP mutant proteins, an ideal approach is to silence the mutant gene in an allele-specific manner and to leave the wildtype allele intact. The challenge, however, are (1) many VCP mutants reported in different locations and (2) obtaining sufficient expression in muscles to target the VCP mutant allele. We recently confirmed the myotropic AAV9 variant, AAVMYO as a promising vector to systematically deliver gene payloads to muscle tissue with liver de-targeting and low immunological response to AAV-transduced muscle tissues in VcpR155H/+ mice. We therefore using this AAVMYO to develop a safe and effective, allele-independent gene therapy approach, co-expression of VCP silencing with rescue vectors to replace endogenous VCP with exogenous functional VCP. We are testing our novel AAV vectors in iPSC-derived myoblasts and VCPR155H/R155H mouse models. Success in these preclinical studies holds potential for promising therapeutic benefits in patients with VCP disease.
Presented by Ashley Cannon, PhD, MS, CGC, InformedDNA
Objective: Clinical trials employing preselection biomarkers have higher success rates. Clinical operations often benefit from genetics expertise to select appropriate genetic tests, identify relevant testing laboratories, and interpret genetic test results for trials with genetic eligibility criteria. 2 Here, we describe the integration of genetic prescreening for a clinical trial to ensure genetic eligibility criteria is met.
Design: Genetic counseling and screening services were integrated into a recruiting and prescreening funnel for a clinical trial targeting a rare neuromuscular disease sponsored by a leading biopharmaceutical company. A patient identification services group functioned as an outsourced clinical research coordinator (CRC). Individuals who met basic criteria, including a clinical diagnosis of the rare disease, were referred to InformedDNA for genetic services.
Results: The CRC recruited 377 individuals and referred 216 to InformedDNA. InformedDNA completed 205 genetic counseling appointments. 164 individuals had previous genetic testing; 16 required updated clinical genetic testing. Genetic testing was ordered for 36 individuals without previous testing. 15 individuals did not meet genetic eligibility criteria, one of these received a genetic diagnosis for a different rare neuromuscular disease. 179 individuals (96% of individuals who met genetic eligibility criteria) elected to be referred to a clinical trial site.
Conclusion: Screening patients for clinical trials with a genetic eligibility component is complex. Genetic experts can efficiently be integrated into the screening workflow to order and review genetic tests. Individuals who receive genetic prescreening are engaged and trial-ready.
Poster Listing - VCP Patient and Care Partner Voice
Below are the poster location and titles for case studies in diagnosis, quality of life, and symptoms of individuals with vasloin containing protein associated multisystem proteinopathy.
-
Poster 41, Todd Warner - Friday Session
-
Poster 42, Camille Knudsen - Friday Session
-
Poster 43, Darla Saul - Thursday Session
-
Poster 44, Brandon Lee - Friday Session
-
Poster 45, Jeannie Macaluso - Thursday Session
-
Poster 46, Penny Wagner - Thursday Session
-
Poster 47, Jan Reimer - Friday Session
-
Poster 48, Brandon Feldt - Thursday Session
-
Poster 49, Allison Peck - Friday Session
Questions?
For questions, please contact us here
bottom of page