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Elucidating the molecular mechanisms of spinocerebellar ataxia gene TMEM16K in interorganellar communication

Award Number: R21AG061468
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/15/2019
PERIOD OF PERFORMANCE END DATE: 11/30/2020

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Elucidating the molecular mechanisms of spinocerebellar ataxia gene TMEM16K in interorganellar communication - Project Summary While it is well established that organelles communicate extensively through vesicular transport, recent work has revealed that essential cellular processes including lipid and calcium homeostasis can be coordinated through evolutionary conserved membrane contact sites (MCS). MCS are maintained by tethering proteins which create specialized microdomains that allow the targeted exchange of ions and lipids between the two membranes. Loss of human orthologs of these proteins have been implicated in a broad range of neurodegenerative diseases. However, the molecular function of these proteins, as well as the mechanisms underlying how such sites of inter- organelle contact regulate cellular physiology and pathophysiology remain to be determined. As an ideal entry- point into this question, we have chosen to study the metazoan ortholog of yeast Ist2, the first established membrane contacts site tether, which encodes a TMEM16K transmembrane protein. Loss of TMEM16K in humans is causative for progressive autosomal recessive spinocerebellar ataxia (SCAR10). We have established that a TMEM16K mouse knockout model recapitulates critical aspects of human disease and have found TMEM16K absence leads to perturbed dendritic morphology in Drosophila neurons. We have further established that endoplasmic reticulum (ER) localized TMEM16K directly binds endolysosomal specific phosphatidylinositols and is required for endolysosomal maturation, suggesting that TMEM16K acts as a critical mediator of ER-endolysosomal inter-organelle communication. Endolysosomal maturation is required for proper sorting and degradation of macromolecules, and is emerging as central player in a host of neurodegenerative diseases. The goal of this proposal is to elucidate the conserved molecular mechanisms through which TMEM16K mediates endolysosomal maturation at ER-endolysosomal membrane contact sites, in order to understand their role in neurodegeneration. To accomplish this, we propose to: (1) Identify the interactome of TMEM16K to reveal molecular pathways perturbed in the disease using novel approach based on proximity biotinylation and mass spectrometry; and (2) Functionally analyze how TMEM16K pathway facilitates endolysosomal maturation in health and disease using an in vivo aged Drosophila neuronal model. Overall, by combining novel technical advancements with comparative biology approaches the implementation of this proposal will define the molecular mechanism of how ER-localized TMEM16K facilitates endolysosomal maturation and contributes to the pathophysiology of neurodegeneration. Considering that such communication at membrane contact sites is emerging as a critical regulatory mechanism for cellular homeostasis, with an increasing number of components linked to neurodegenerative disease, their better understanding could also open new avenues for novel therapeutics. .


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: 2021 ( Subtotal = $0 )
2021	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Aging Research	000	2	4/19/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $241,004 )
2020	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Aging Research	001	2	1/28/2020	NON-COMPETING CONTINUATION	$24,101
2020	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Aging Research	000	2	12/2/2019	NON-COMPETING CONTINUATION	$216,903
														Subtotal = $241,004

Issue Date FY: 2019 ( Subtotal = $200,106 )
2019	2019	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Aging Research	000	1	2/6/2019	NEW	$200,106
														Subtotal = $200,106

Grand Total All Awards = $441,110

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Elucidating the molecular mechanisms of spinocerebellar ataxia gene TMEM16K in interorganellar communication

Award Number: R21AG061468

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 02/15/2019

PERIOD OF PERFORMANCE END DATE: 11/30/2020

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