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DISSECTING THE ROLE OF TMEM163 PROTEIN IN CELLS

Award Number: R15NS101594
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2017
PERIOD OF PERFORMANCE END DATE: 01/31/2024

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DISSECTING THE ROLE OF TMEM163 PROTEIN IN CELLS - PROJECT SUMMARY/ABSTRACT Mucolipidosis type IV (MLIV) is a lysosomal storage disorder that mainly affects the brain, eyes, and stomach. The disease is caused by a loss of function mutation in the TRPML1 ion channel. We discovered abnormally high zinc levels in lysosomes of MLIV patient fibroblasts and cell culture model of MLIV. Moreover, we found elevated zinc levels in cortical brain tissues taken from the mucolipin-1 knockout (Mcoln1–/– KO) MLIV mouse model. In an attempt to explain zinc imbalance in MLIV, we identified a TRPML1 interaction partner called Transmembrane (TMEM)-163 that happens to bind and transport zinc. The main goal of the previous R15 grant is to characterize the role of TMEM163 and its relevance to MLIV. The data arising from the project show for the first time that TMEM163 is a zinc efflux transporter. Interestingly, we also found that TMEM163 interacts with ZNT4, a zinc transporter implicated by another lab as responsible for lysosomal zinc accumulation upon knockdown of TRPML1 in cultured cells. Zinc flux assays of the TMEM163-ZNT4 heterodimer slightly differed from homodimeric TMEM163, suggesting that the interaction may modulate TMEM163's function. Meanwhile, RNA sequencing (RNA-seq) of cortical brain tissues from Mcoln1–/– KO and wild-type littermate mice revealed that mouse Tmem163 and several ZnT (Slc30) zinc transporters transcripts are prominently down-regulated. Thus, we hypothesize that TMEM163 and specific zinc transporters may potentially contribute to MLIV pathology. The main goal of this R15 renewal is to further dissect the roles of TMEM163 and other zinc transporters in MLIV disease. The first aim will investigate the interaction and functional difference between TMEM163 and ZNT2 (lysosomal zinc) transporter, and TMEM163 and ZNT3 (vesicular zinc) transporter based on the fact that these related proteins have similar function as ZNT4 and localize within membrane compartments. Secondly, we aim to validate our initial findings of differentially expressed Tmem163 and ZnT (Slc30) zinc transporter genes from Mcoln1–/– brain tissues. Validation of the RNA-seq data could help explain the mechanistic processes underlying zinc dyshomeostasis in MLIV cells. Finally, we aim to screen and identify drugs that will augment or inhibit the efflux activity of TMEM163 for use in functional assays or potential therapeutics. Ultimately, the data that will be gathered from this proposal would fill current gaps in our knowledge on the physiological and pathological roles contributed by TMEM163 and other zinc transporters in the etiology and disease progression underlying intracellular or lysosomal zinc accumulation MLIV and other neurodegenerative diseases.


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: 2024 ( Subtotal = -$2,158 )
2024	2020	CSU FULLERTON AUXILIARY SERVICES CORPORATION	1121 N STATE COLLEGE BLVD	FULLERTON	CA	92831	ORANGE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	6/12/2024	COMPETING CONTINUATION	-$2,158
														Subtotal = -$2,158

Issue Date FY: 2020 ( Subtotal = $394,854 )
2020	2020	CSU FULLERTON AUXILIARY SERVICES CORPORATION	1121 NORTH STATE COLLEGE BOULEVARD	FULLERTON	CA	92831	ORANGE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	2	7/10/2020	COMPETING CONTINUATION	$4,280
2020	2020	CSU FULLERTON AUXILIARY SERVICES CORPORATION	1121 NORTH STATE COLLEGE BOULEVARD	FULLERTON	CA	92831	ORANGE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	2/12/2020	COMPETING CONTINUATION	$394,854
2020	2017	CSU FULLERTON AUXILIARY SERVICES CORPORATION	1121 NORTH STATE COLLEGE BOULEVARD	FULLERTON	CA	92831	ORANGE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	1	7/10/2020	NEW	-$4,280
2020	2017	CSU FULLERTON AUXILIARY SERVICES CORPORATION	1121 NORTH STATE COLLEGE BOULEVARD	FULLERTON	CA	92831	ORANGE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	2/12/2020	NEW	$0
														Subtotal = $394,854

Issue Date FY: 2017 ( Subtotal = $382,074 )
2017	2017	CSU FULLERTON AUXILIARY SERVICES CORPORATION	1121 NORTH STATE COLLEGE BOULEVARD	FULLERTON	CA	92831	ORANGE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	1/27/2017	NEW	$382,074
														Subtotal = $382,074

Grand Total All Awards = $774,770

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DISSECTING THE ROLE OF TMEM163 PROTEIN IN CELLS

Award Number: R15NS101594

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/01/2017

PERIOD OF PERFORMANCE END DATE: 01/31/2024

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