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Mechanism and rescue of lysosomal defects in Adult-onset Neuronal Ceroid Lipofuscinosis

Award Number: F31NS143430
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 09/22/2025
PERIOD OF PERFORMANCE END DATE: 07/22/2027

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Mechanism and rescue of lysosomal defects in Adult-onset Neuronal Ceroid Lipofuscinosis - PROJECT SUMMARY Adult-onset neuronal ceroid lipofuscinosis (ANCL) is a fatal lysosomal storage disorder known to be caused by autosomal dominant mutations (CSPαL115R, CSPαL116del) in the gene encoding cysteine string protein-alpha (CSPα). There are currently no treatments that can reverse or slow ANCL progression, which leads to progres- sive cognitive and motor impairment, epileptic seizures, dementia, and premature death. CSPα has no estab- lished connection to lysosomal function and is known to form a chaperone complex with SGT (small glutamine- rich tetratricopeptide repeat-containing protein) and Hsp70/Hsc70 (heat shock protein/cognate protein 70 kDa), which chaperones the synaptic SNARE protein SNAP-25. My preliminary data establishes SNAP-23, a homo- log of SNAP-25, as a previously unknown client of the CSPα/SGT/Hsc70 chaperone complex. This interaction was found via (i) immunoprecipitation of CSPα from wild type mouse brain followed by tandem mass spectrom- etry identification of SNAP-23, (ii) reduced SNAP-23 protein levels in CSPα knockout (CSPα-/-) mouse brains, and (iii) co-immunoprecipitation of SNAP-23 with each member of the CSPα/SGT/Hsc70 chaperone complex. Importantly, SNAP-23 forms a SNARE-complex with VAMP7 and syntaxin-4, the formation of which mediates Ca2+-dependent lysosomal exocytosis. Accordingly, I found diminished Ca2+-dependent lysosomal exocytosis in CSPα-/- primary neurons by measuring cell surface exposure of the LAMP-1 luminal domain. This preliminary data provides a novel, direct link between ANCL mutations in CSPα and the lysosomal pathology observed in ANCL, via impaired SNAP-23 function. The proposed study aims to (a) delineate the specific molecular mecha- nism(s) by which CSPα mutations impair SNAP-23 function, leading to the lysosomal pathology of ANCL, and (b) to evaluate the lysosomal SNARE-protein SNAP-23, a novel client of the CSPα/SGT/Hsc70 chaperone complex, as a potential therapeutic target for ANCL. I hypothesize that ANCL-causing mutations CSPαL115R and CSPαL116del reduce the ability of the CSPα/SGT/Hsc70 complex to effectively chaperone lysosomal SNARE protein SNAP-23, leading to defects in SNARE-complex assembly and lysosomal exocytosis which can be rescued by increasing SNAP-23 protein levels. In this proposal, aim 1 will examine how ANCL-causing mutations in CSPα impact the ability of the CSPα/SGT/Hsc70 complex to chaperone SNAP-23, and how loss of CSPα chaperone activity impacts SNAP-23 stability, lysosomal SNARE-complex assembly, and lysosomal exocytosis. Aim 2 will evaluate the potential of genetic and pharmacological strategies that in- crease SNAP-23 protein levels to rescue (a) SNARE-complex and lysosomal defects resulting in primary neu- rons from CSPα-/- mice and (b) premature lipofuscinosis and neurodegeneration in CSPα-/- mice. Successful completion of these studies will inform the development of rational therapeutic strategies for ANCL patients.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $45,220 )
2026	2026	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	8/12/2026	NON-COMPETING CONTINUATION	$45,220
														Subtotal = $45,220

Issue Date FY: 2025 ( Subtotal = $49,538 )
2025	2025	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	9/25/2025	NEW	$0
2025	2025	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	9/22/2025	NEW	$49,538
														Subtotal = $49,538

Grand Total All Awards = $94,758

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Mechanism and rescue of lysosomal defects in Adult-onset Neuronal Ceroid Lipofuscinosis

Award Number: F31NS143430

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 09/22/2025

PERIOD OF PERFORMANCE END DATE: 07/22/2027

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