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  • Cure VCP Disease, Inc.

Dr. Eileen Lynch Wins 2024 Young Investigator Award


We are pleased to announce that Dr. Eileen Lynch, PhD, is our 2024 Young Investigator Award (YIA) winner for her work on "The role of VCP in TDP-43 proteopathic seeding." Dr. Lynch is a post doctoral research associate at the Weihl Lab, Department of Neurology, Washington University in St. Louis. As part of the recognition, Dr. Lynch will be a speaker at the 2024 VCP International Conference.


The YIA recognizes an outstanding post-doctoral scientist who has contributed exceptionally to the VCP field, either in the structure and function of VCP, translational research, or clinical research. Dr Lynch's work demonstrated the best ability regarding the methodology, results quality, conclusions, level of innovation, and Impact on the VCP field, as evaluated by a jury of Key Opinion Leaders.


 

Summary of Awarded Work: The role of VCP in TDP-43 proteopathic seeding


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.


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