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Aggregation and TDP-43-associated mitochondrial dysfunction and neurodegeneration

Award Number: R01NS148267
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: 08/15/2026
PERIOD OF PERFORMANCE END DATE: 07/31/2031

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Aggregation and TDP-43-associated mitochondrial dysfunction and neurodegeneration - PROJECT SUMMARY Autosomal dominant mutations in TDP-43 are causally linked to amyotrophic lateral sclerosis (ALS), a neurodegenerative disease marked by progressive motor neuron degeneration. Beyond ALS, TDP-43 proteinopathy—characterized by pathological mislocalization of TDP-43 from the nucleus to the cytoplasm—is a hallmark of both familial and sporadic ALS, as well as frontotemporal dementia (FTD), Alzheimer’s disease (AD), limbic-predominant age-related TDP-43 encephalopathy (LATE), and cerebral age-related TDP-43 with sclerosis (CARTS). TDP-43 is strongly linked to brain atrophy in AD and related dementias (ADRDs), where its dysregulation impairs nuclear and mitochondrial function, contributing to neuronal toxicity and degeneration. In parallel, our previous genome-wide association study identified a single nucleotide polymorphism (SNP) in FAM222A, a gene encoding the protein Aggregatin, which has also been associated with AD-related brain atrophy. Aggregatin exhibits dual localization to both the nucleus and mitochondria via its nuclear localization signal and mitochondrial targeting sequence. This positioning suggests Aggregatin may be an integrator of signals between mitochondria and the nucleus for inter-organelle communication in AD and ADRDs. Interestingly, Aggregatin was found to interact with TDP-43, mediating its aggregation and toxicity. This study aims to build on these findings by exploring how Aggregatin regulates TDP-43 mitochondrial and neuronal toxicity through its dual functions in the nucleus and mitochondria. The research will use Aggregatin knockout models to investigate its influence on TDP-43-mediated mitochondrial dysfunction and neuronal toxicity and mitochondrial-nuclear communication, with the goal of uncovering new pathways driving neurodegeneration. Given the increasing recognition of mitochondrial dysfunction as a central feature of neurodegenerative diseases, this study could provide valuable insights into how proteins like Aggregatin, which localize to both organelles, integrate cellular stress responses. Understanding how Aggregatin regulates TDP-43 toxicity could offer new therapeutic targets for ALS, AD, FTD, LATE, and other neurodegenerative diseases. The unique dual localization of Aggregatin to mitochondria and the nucleus makes it an ideal candidate for investigating mitochondrial-nuclear communication and its role in TDP-43 proteinopathy. Very few proteins exhibit such dual localization, and Aggregatin's ability to modulate both nuclear and mitochondrial pathways suggests it may be an important factor in understanding mitochondrial-nuclear communication, a crucial aspect increasingly recognized in neurodegeneration.


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 = $530,105 )
2026	2026	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	8/12/2026	NEW	$530,105
														Subtotal = $530,105

Grand Total All Awards = $530,105

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Aggregation and TDP-43-associated mitochondrial dysfunction and neurodegeneration

Award Number: R01NS148267

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: 08/15/2026

PERIOD OF PERFORMANCE END DATE: 07/31/2031

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