University of Connecticut

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Neuroscience Seminar Series - Sharma

Thursday, January 23, 2020
11:00am – 12:00pm

UConn Health
Low Learning Center

Sponsored by the Kim Family Fund

"An Unusual Mechanism of Pathogenic Aggregation of Cysteine String Protein-α (CSPα)"

Manu Sharma, PhD Assistant Professor of Neuroscience, Weill Cornell Medical College, Appel Institute for Alzheimer's Research, and Brain & Mind Research Institute, New York, NY

ABSTRACT Point mutations in cysteine string protein-α (CSPα) cause dominantly inherited adult-onset neuronal ceroid lipofuscinosis (ANCL) – a rapidly progressing and lethal neurodegenerative disease with no available treatment. Recent studies have proposed that ANCL-causing mutations lead to CSPα aggregation/oligomerization, but the mechanism of oligomer formation remains unclear. Here we show that the cysteine string region of CSPα, which is normally palmitoylated, loses palmitoylation due to the ANCL mutations; allowing oligomerization of mutant CSPα via ectopic iron-sulfur (Fe-S) cluster-binding. Whereas the wild type CSPα forms a synaptic chaperone complex with Hsc70 and SGT, the mutant CSPα is misrecognized by an Fe-S cluster-loading complex comprising Hsc70 and ISCU. The resulting oligomerization of mutant CSPα causes deficiency in its SNARE-chaperoning function, leading to reduced levels of the neuronal SNARE protein SNAP-25, and reduced SNARE-complex assembly. We then find that we can partially rescue the palmitoylation-deficiency and oligomerization of mutant CSPα, as well as the consequent SNARE defects and the pathological hallmark of lipofuscin accumulation, by pharmacologically chelating iron in mouse primary neurons and in patient-derived induced neurons. Thus, the iron-chelators deferiprone (L1) and deferoxamine (Dfx), both already in human use for treating iron-overload, offer a novel approach for treating ANCL.

Host: Dr. David Martinelli, david.martinelli@uchc.edu

Contact:

Jody Gridley, gridley@uchc.edu, 860-679-8787

Neuroscience Department at UConn Health (primary), School of Medicine, UConn Health Master Calendar

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