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The Role of TMEM106B in FTLD-TDP Pathogenesis

Award Number: F30AG085984
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 12/06/2023
PERIOD OF PERFORMANCE END DATE: 06/05/2027

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The Role of TMEM106B in FTLD-TDP Pathogenesis - PROJECT SUMMARY/ABSTRACT Alzheimer disease and related dementias (ADRD) comprise a group of neurodegenerative diseases characterized by progressive decline of cognitive, behavioral, and/or motor function. These conditions place a significant burden on patients, families, and the healthcare system. Among the ADRDs is frontotemporal dementia (FTD), with approximately half of FTD cases characterized pathologically by frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP). Single nucleotide polymorphisms (SNPs) in TMEM106B are known to alter risk of FTLD-TDP. TMEM106B is a protein localized to late endosomes and lysosomes and has been reported to play a role in endolysosomal trafficking and brain myelination. Only one TMEM106B SNP causes a coding change, altering the amino acid at position 185 from threonine to serine (T185S). The TT185 haplotype is associated with significantly increased risk of FTLD-TDP relative to SS185. The SNP is also in high linkage disequilibrium with other TMEM106B SNPs, marking the coding change as a potential mechanism behind TMEM106B’s modulation of disease risk. The coding SNP of TMEM106B has not been studied extensively, though the coding change has been reported to alter protein half-life and autophagic flux in the cell. Recently, four groups published the discovery of TMEM106B amyloid fibrils in sarkosyl-insoluble cortical lysates across a range of neurodegenerative diseases, including FTLD-TDP. In preliminary studies, we have observed that accumulation of TMEM106B fibrils is positively associated with the TT185 haplotype. We speculate that the TMEM106B risk haplotype drives fibril formation and endolysosomal dysfunction, both of which contribute to neuron loss in disease. The studies outlined in this proposal will characterize the biological consequences of TMEM106B fibril formation in the diseased human brain and investigate TMEM106B haplotype-specific differences in endolysosomal function in a new cell model system. In Aim 1, we will identify protein interactors of TMEM106B fibrils in postmortem FTLD-TDP and non-diseased brains to test the hypothesis that TMEM106B fibrils exhibit disease-specific interactions that drive neuron loss. In Aim 2, mechanistic studies will be performed in novel, isogenic iPSC-derived neuron models stably expressing TMEM106B coding variants to test the hypothesis that the TMEM106B risk haplotype impairs endolysosomal function. We will also assess mechanistic relationships between TMEM106B and top interactors identified in Aim 1, and how they may vary with TMEM106B haplotype. We anticipate that this work will help identify novel protein targets to investigate or target for therapeutic development.


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 = $50,314 )
2026	2026	MAYO CLINIC JACKSONVILLE (A NONPROFIT CORPORATION)	4500 SAN PABLO RD S	JACKSONVILLE	FL	32224	DUVAL	USA	Aging Research	000	3	1/16/2026	NON-COMPETING CONTINUATION	$49,738
2026	2026	MAYO CLINIC JACKSONVILLE (A NONPROFIT CORPORATION)	4500 SAN PABLO RD S	JACKSONVILLE	FL	32224	DUVAL	USA	Aging Research	001	3	3/25/2026	NON-COMPETING CONTINUATION	$576
														Subtotal = $50,314

Issue Date FY: 2025 ( Subtotal = $49,738 )
2025	2025	MAYO CLINIC JACKSONVILLE (A NONPROFIT CORPORATION)	4500 SAN PABLO RD S	JACKSONVILLE	FL	32224	DUVAL	USA	Aging Research	001	2	6/23/2025	NON-COMPETING CONTINUATION	$564
2025	2025	MAYO CLINIC JACKSONVILLE (A NONPROFIT CORPORATION)	4500 SAN PABLO RD S	JACKSONVILLE	FL	32224	DUVAL	USA	Aging Research	000	2	11/15/2024	NON-COMPETING CONTINUATION	$49,174
														Subtotal = $49,738

Issue Date FY: 2024 ( Subtotal = $49,174 )
2024	2024	MAYO CLINIC JACKSONVILLE (A NONPROFIT CORPORATION)	4500 SAN PABLO RD S	JACKSONVILLE	FL	32224	DUVAL	USA	Aging Research	000	1	12/6/2023	NEW	$47,894
2024	2024	MAYO CLINIC JACKSONVILLE (A NONPROFIT CORPORATION)	4500 SAN PABLO RD S	JACKSONVILLE	FL	32224	DUVAL	USA	Aging Research	002	1	4/30/2024	NEW	$0
2024	2024	MAYO CLINIC JACKSONVILLE (A NONPROFIT CORPORATION)	4500 SAN PABLO RD S	JACKSONVILLE	FL	32224	DUVAL	USA	Aging Research	001	1	4/30/2024	NEW	$1,280
														Subtotal = $49,174

Grand Total All Awards = $149,226

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The Role of TMEM106B in FTLD-TDP Pathogenesis

Award Number: F30AG085984

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 12/06/2023

PERIOD OF PERFORMANCE END DATE: 06/05/2027

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