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REGULATION OF PROTEOSTASIS AND TAUOPATHY BY MALTOSE-INDUCED SIGNALING

Award Number: R01AG075869
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2024
PERIOD OF PERFORMANCE END DATE: 02/28/2029

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REGULATION OF PROTEOSTASIS AND TAUOPATHY BY MALTOSE-INDUCED SIGNALING - PROJECT SUMMARY Proper signaling is necessary for homeostasis in multicellular organisms. Once considered mere byproducts of cellular metabolism, small metabolites have now emerged as an important class of signaling factors that regulate tissue and whole-body functions. However, the role of small metabolites in proteostasis and age-related neurodegeneration is largely unexplored. We have recently found that the disaccharide maltose and the maltose- producing amylase enzyme Amyrel preserve proteostasis of the central nervous system (CNS) during aging in Drosophila. Specifically, Amyrel and maltose protect from tauopathy and prevent the age-related accumulation of poly-ubiquitinated proteins in the brain and retina during aging via the transcriptional induction of chaperones. Conversely, knockdown of SLC45 maltose transporters reduces the expression of Amyrel-induced chaperones and worsens brain proteostasis and tauopathy. Moreover, maltose preserves proteostasis and neuronal activity in human brain organoids challenged by thermal stress. Altogether, these findings indicate that maltose is a novel, conserved regulator of CNS proteostasis. However, the mechanisms via which maltose preserves proteostasis are incompletely understood and it remains unexplored how maltose impacts proteostasis across cell compartments. Specifically, although maltose is a chemical chaperone, many small metabolites are now known to act as signaling factors. This raises the question on whether maltose regulates proteostasis via signaling mechanisms independent from its chemical chaperone activity. In agreement with this hypothesis, our preliminary studies now identify the transcription factor Broad as a possible mediator of maltose-induced chaperone expression and CNS proteostasis during aging. On this basis, we propose the following aims: to determine the mechanisms via which Amyrel/SLC45 protects from neurodegeneration and functional decline induced by pathogenic tau/MAPT (aim 1); to determine the impact of Amyrel/SLC45 on proteostasis in different subcellular compartments (aim 2); and to determine whether Amyrel/SLC45 signaling regulates CNS proteostasis and tauopathy via the transcription factor Broad (aim 3). Altogether, these studies promise to provide fundamental understanding of a novel maltose-induced signaling pathway that preserves brain proteostasis during aging and that protects from tauopathy. Knowledge gained from these studies will guide the design of effective therapies to preserve and/or reinstate proteostasis in patients with tauopathies and Alzheimer’s disease.


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: 2025 ( Subtotal = $453,250 )
2025	2025	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Aging Research	000	2	1/23/2025	NON-COMPETING CONTINUATION	$416,250
2025	2025	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Aging Research	001	2	8/4/2025	NON-COMPETING CONTINUATION	$37,000
														Subtotal = $453,250

Issue Date FY: 2024 ( Subtotal = $461,875 )
2024	2024	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Aging Research	001	1	5/30/2024	NEW	$6,875
2024	2024	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Aging Research	000	1	5/22/2024	NEW	$455,000
														Subtotal = $461,875

Grand Total All Awards = $915,125

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REGULATION OF PROTEOSTASIS AND TAUOPATHY BY MALTOSE-INDUCED SIGNALING

Award Number: R01AG075869

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/2024

PERIOD OF PERFORMANCE END DATE: 02/28/2029

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