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Characterization and Rescue of Premature Degradation in Neurodegeneration-Associated TRPML1 Mutants

Award Number: F31AG104749
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 03/10/2027
PERIOD OF PERFORMANCE END DATE: 03/09/2028

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Characterization and Rescue of Premature Degradation in Neurodegeneration-Associated TRPML1 Mutants - PROJECT SUMMARY Lewy body disease (LBD) is a spectrum of age-related neurodegenerative disorders frequently co-occurring with Alzheimer’s and Parkinson’s disease and is characterized by progressive dementia and the presence of intraneuronal aggregates called Lewy bodies. Mucolipidosis Type IV (MLIV) is a lysosomal storage disorder with an infantile onset followed by progressive neurodegeneration with most patients suffering from blindness, intellectual disability, and inability to walk independently. No disease-modifying therapies exist for either LBD or MLIV, and both of these neurodegenerative disorders have ties to the protein TRPML1, a lysosomal cation channel that releases Ca2+ from the lysosomal lumen to the cytosol. Loss-of-function mutations in MCOLN1, which encodes TRPML1, are causal for MLIV, and additional variants of MCOLN1 have been associated with neuropathologically confirmed LBD in a gene-wise study. The precise mechanisms by which TRPML1 muta- tions lead to neurodegeneration remain unclear, as TRPML1-mediated Ca2+ release serves many functions within the cell, including initiating lysosomal exocytosis which contributes to cellular clearance. In addition, LBD-associated variants have not been characterized, defining a key knowledge gap of their localization and functional activity. The channel activity of prematurely degraded MLIV-causal mutants is also unknown, as these mutants do not exhibit lysosomal localization. Improving their localization could provide sufficient TRPML1 activity to enhance clearance and ameliorate MLIV pathology. Chemical chaperones, which act as proteostasis regulators to reduce misfolding and endoplasmic reticulum-associated degradation, have shown positive impacts on mutant protein localization in cystic fibrosis and Gaucher Disease, but have not been tested in mutant TRPML1. This study will evaluate the hypothesis that TRPML1 mutations lead to prema- ture protein degradation, causing mislocalization and depletion of functional channel pools which can be rescued by chemical chaperone treatment. To test this, Aim 1 will use immunoblotting, immunocyto- chemistry, live-cell calcium imaging, and lysosomal exocytosis assays in primary cortical cells to characterize the localization and function of LBD-associated TRPML1 variants. Aim 2 will test small molecule chemical chaperones in MLIV patient fibroblasts for their ability to restore localization and function of prematurely de- graded MLIV-causal TRPML1 mutants. This fellowship will provide rigorous training in live-cell imaging, quanti- tative analysis, and scientific communication skills, in a well-suited research environment complete with co- sponsors’ strengths in molecular neurodegeneration, high-quality imaging equipment, and abundant institu- tional resources. Completion of this research will clarify the link between lysosomal dysfunction and neuro- degeneration and identify therapeutic strategies to rescue mutant TRPML1 functional pools which may be ap- plied to other disorders caused by premature protein degradation. Together, these studies on TRPML1 will elucidate mechanisms and treatments for severely disabling neurodegenerative disorders.


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 = $50,114 )
2026	2026	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Aging Research	000	1	9/10/2026	NEW	$50,114
														Subtotal = $50,114

Grand Total All Awards = $50,114

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Characterization and Rescue of Premature Degradation in Neurodegeneration-Associated TRPML1 Mutants

Award Number: F31AG104749

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 03/10/2027

PERIOD OF PERFORMANCE END DATE: 03/09/2028

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