Tuesday, October 21, 2025 10/21/2025

Role of ATAD3A in Lysosomal Homeostasis and Neurogenesis

Award Number: R01NS121298
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: 09/01/2021
PERIOD OF PERFORMANCE END DATE: 08/31/2026

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Role of ATAD3A in Lysosomal Homeostasis and Neurogenesis - PROJECT SUMMARY/ABSTRACT ATAD3A (ATP family AAA-domain containing protein 3A) is a mitochondrial membrane protein that is implicated in mitochondrial membrane dynamics. We discovered that dominant mutations in ATAD3A cause a human neurological syndrome characterized by early-onset peripheral neuropathy, optic atrophy and mild brain malformation. Patients with loss of function mutations in ATAD3A continue to be identified, presenting with severe neurodevelopmental defects, supporting the importance of this protein in human health. However, the root cause of this syndrome at the cellular and molecular levels, as well as strategies to ameliorate the symptoms remain unsolved issues. Our long-term goal is to determine the roles of ATAD3A in development and in metabolic homeostasis as the basis for therapies to treat patients suffering from ATAD3A-associated diseases. The objective of our proposal is to uncover the mechanisms by which ATAD3A controls nutrition sensing (i.e. mTORC1), lysosomal biogenesis and neuronal development using Drosophila and ATAD3A patient-derived induced pluripotent stem cells. Our Central Hypothesis is that ATAD3A plays a key role in mTORC1 signaling and lysosomal biogenesis through Rag GTPase modulation, and that ATAD3A-dependent nutrition sensing and lysosomal homeostasis are required for proper neurogenesis and development based on the following compelling evidence. Briefly, using IP-mass spec and co-IP, we identified endogenous binding partners of ATAD3A, including the lysosomal proteins RagD, a GTPase required for activating mTORC1, and MiT-TFE proteins, transcriptional factors for lysosomal biogenesis. We found that ATAD3A forms a complex with active Rag GTPases and MiT-TFE proteins. This finding helped explain our discovery that Drosophila bearing a dominant negative ATAD3A mutation (R528W) exhibit defects in nutrition sensing (implicating Rag/mTORC1), and aberrantly elevated lysosomal content in developing neurons (implicating MITF). In Drosophila, we found that ATAD3A null mutations caused embryonic lethality with abnormal patterning and morphology of central and peripheral neurons. In addition, we found that the sizes of brain organoids derived from the patient iPSCs are significantly smaller than those derived from isogenic controls. We will test our central hypothesis by performing the following Specific Aims: (1) to determine how ATAD3A regulates mTORC1 signaling; (2) to determine how ATAD3A mutations lead to abnormal lysosomal biogenesis in neurons; (3) to determine how ATAD3A loss causes neurogenesis defects. These studies will characterize a novel axis of mitochondria-lysosomal-mTORC1 signaling that should reveal novel molecular insights into the cellular defects in patient neurons that underlie ATAD3A-associated neurological diseases. We anticipate the identification of potential therapeutic targets for neurological diseases associated not only with ATAD3A mutations, but also with defects in mitochondrial and lysosomal homeostasis.


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 = $433,300 )
2025	2025	OKLAHOMA MEDICAL RESEARCH FOUNDATION	825 NE 13TH ST	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	8/14/2025	NON-COMPETING CONTINUATION	$433,300
														Subtotal = $433,300

Issue Date FY: 2024 ( Subtotal = $420,301 )
2024	2024	OKLAHOMA MEDICAL RESEARCH FOUNDATION	825 NE 13TH ST	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	8/12/2024	NON-COMPETING CONTINUATION	$420,301
														Subtotal = $420,301

Issue Date FY: 2023 ( Subtotal = $433,300 )
2023	2023	OKLAHOMA MEDICAL RESEARCH FOUNDATION	825 NE 13TH ST	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	8/18/2023	NON-COMPETING CONTINUATION	$433,300
														Subtotal = $433,300

Issue Date FY: 2022 ( Subtotal = $433,300 )
2022	2022	OKLAHOMA MEDICAL RESEARCH FOUNDATION	825 NE 13TH ST	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	8/9/2022	NON-COMPETING CONTINUATION	$433,300
														Subtotal = $433,300

Issue Date FY: 2021 ( Subtotal = $452,000 )
2021	2021	OKLAHOMA MEDICAL RESEARCH FOUNDATION	825 NE 13TH ST	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	5/28/2021	NEW	$452,000
														Subtotal = $452,000

Grand Total All Awards = $2,172,201

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Role of ATAD3A in Lysosomal Homeostasis and Neurogenesis

Award Number: R01NS121298

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: 09/01/2021

PERIOD OF PERFORMANCE END DATE: 08/31/2026

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