Valosin containing protein (VCP) is the causative gene for several degenerative diseases, including frontotemporal dementia and ALS, but the molecular mechanisms underlying VCP diseases are unknown. To investigate potential mechanisms of VCP-mediated cellular degeneration, we are using CRISPR knock-in genome engineering to generate endogenous gene replacements of VCP disease mutations in Drosophila. The major hallmark of VCP diseases is the abnormal accumulation of toxic protein aggregates in the cytoplasm, hinting at a defect in protein clearance mechanisms. Recently, we and other labs have found that several VCP disease mutations are linked to defects in autophagy-mediated degradation. We are now investigating how VCP disease mutations disrupt autophagy-dependent protein clearance. In our initial studies, we made a surprising discovery that lysosomes do not purely exist as vesicular structures, as they are classically viewed, but form expansive tubular structures in multiple cell types, including muscles and glia. These unique lysosomal organelles require VCP for their formation and/or maintenance, as over-expression of several disease-causing VCP mutations collapse the tubular architecture of lysosomes and consequently disrupt autophagosome-lysosome fusion. We hypothesize that disruption of lysosome tubules is a direct cause of the autophagy defects observed in VCP-associated diseases. The broad objectives of this proposal are: (1) to identify the molecular mechanisms by which VCP supports lysosome structure and function in normal, healthy cells; and (2) to clarify how these functions are disrupted in disease states.

Public Health Relevance

Mutations in Valosin containing protein (VCP) cause several degenerative diseases, including frontotemporal dementia and ALS. To study how VCP mutations cause degeneration, we are introducing the disease-causing VCP mutations in fruit flies to mimic the human diseases. We anticipate the results from our studies to reveal new targets for the treatment of several degenerative diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Career Transition Award (K99)
Project #
1K99NS100988-01
Application #
9292962
Study Section
Neurological Sciences Training Initial Review Group (NST)
Program Officer
Miller, Daniel L
Project Start
2017-05-01
Project End
2017-12-31
Budget Start
2017-05-01
Budget End
2017-12-31
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Biochemistry
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94118