Monday, July 7, 2025 7/7/2025

Translation dysregulation in neurodegeneration

Award Number: R01NS091299
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: 06/01/2025
PERIOD OF PERFORMANCE END DATE: 05/31/2027

Group Awards By:

View Award Description

Translation dysregulation in neurodegeneration - Amyotrophic lateral sclerosis (ALS) and fronto-temporal dementia (FTD) comprise a spectrum disorder characterized by progressive neuronal degeneration. A pathological hallmark of ALS/FTD is the presence of cytoplasmic aggregates containing the RNA binding protein TDP-43 (97% of ALS and 45% of FTD cases). To elucidate the molecular underpinnings of ALS/FTD, we developed Drosophila models of TDP-43 proteinopathy based on overexpression of human TDP-43 in motor neurons (ALS) or mushroom body (MB) neurons (FTD). These models exhibit remarkable similarities to the human disease, including cytoplasmic aggregates (ALS/FTD), neuromuscular deficits accompanied by locomotor dysfunction and reduced lifespan (ALS) as well as memory and sleep deficits (FTD). Using ALS fly models we identified phenotypes that were subsequently validated in patient derived iPSC motor neurons (iPSC MNs) or spinal cords, including alterations in the microtubule associated protein Futsch/MAP1B and the synaptic vesicle chaperone Hsc70-4/HSPA8. These findings support the ribostasis hypothesis, which posits that in disease, TDP-43 mis-localizes to the cytoplasm where it sequesters RNAs rendering them unavailable to ribosomes for translation. To further probe this hypothesis we used a combination of RNA ImmunoPrecipitations (RIP) and Tagged Ribosome Affinity Purifications (TRAP) in fly models of TDP-43 proteinopathy. Functional annotation tools highlight multiple targets and pathways with altered ribostasis in TDP-43 proteinopathy, including dally-like protein (Dlp/GPC6), a regulator of trans-synaptic signaling and plasticity at the neuromuscular junction (NMJ) and a risk factor for Alzheimer’s Disease. We found that Dlp/GPC6 is reduced at the fly NMJ but accumulates in the ventral nerve cord in flies, and ALS patient iPSC MNs and spinal cords. Interestingly, Dlp is significantly reduced in Drosophila MBs in an age dependent manner. Taken together, our published work and these findings led us to hypothesize that TDP- 43 toxicity in neurons is caused in part by translation dysregulation of specific mRNA targets including Dlp/GPC6. To test this hypothesis we will use genetic and molecular approaches in flies to elucidate the mechanism by which Dlp/GPC6 contributes to TDP-43 dependent, neuronal and synaptic dysfunction in ALS. These findings will be validated in patient derived iPSC MNs, NMJs and tissues (Aim 1). We will also establish the contribution of Dlp/GPC6 to FTD using flies and patient derived cortical neurons (CNs), organoids and tissues (Aim 2). Finally, we will use Non-Canonical Aminoacid Tagging (NCAT) in vivo, in flies to identify specific, TDP- 43 dependent changes in new protein synthesis that will be validated in iPSC NMJs and organoids. These studies in ALS and FTD relevant models are expected to fill a critical gap of knowledge, on TDP-43’s role in translation, to mechanistically determine the basis of axonal and synaptic dysfunction in TDP-43 proteinopathy, to provide an opportunity for probing neuronal specific vulnerabilities and may uncover novel molecular targets and pathways with therapeutic potential for ALS/FTD.


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 = $707,634 )
2025	2025	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	8	6/6/2025	EXTENSION WITH OR WITHOUT FUNDS	$707,634
														Subtotal = $707,634

Issue Date FY: 2024 ( Subtotal = -$21,476 )
2024	2019	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	1/8/2024	NON-COMPETING CONTINUATION	-$21,476
														Subtotal = -$21,476

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2019	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	2/3/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2019	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	8/6/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $699,895 )
2019	2019	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	6/12/2019	NON-COMPETING CONTINUATION	$321,921
2019	2019	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	9/12/2019	SUPPLEMENT FOR EXPANSION	$377,974
														Subtotal = $699,895

Issue Date FY: 2018 ( Subtotal = $321,921 )
2018	2018	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	4/30/2018	NON-COMPETING CONTINUATION	$321,921
														Subtotal = $321,921

Issue Date FY: 2017 ( Subtotal = $321,921 )
2017	2017	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	4/26/2017	NON-COMPETING CONTINUATION	$289,728
2017	2017	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	5/26/2017	NON-COMPETING CONTINUATION	$32,193
														Subtotal = $321,921

Issue Date FY: 2016 ( Subtotal = $321,848 )
2016	2016	UNIVERSITY OF ARIZONA	POST OFFICE BOX 3308	TUCSON	AZ	85722		USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	5/4/2016	NON-COMPETING CONTINUATION	$321,848
														Subtotal = $321,848

Issue Date FY: 2015 ( Subtotal = $334,296 )
2015	2015	UNIVERSITY OF ARIZONA	POST OFFICE BOX 3308	TUCSON	AZ	85722		USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	8/24/2015	NEW	$334,296
														Subtotal = $334,296

Grand Total All Awards = $2,686,039

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Translation dysregulation in neurodegeneration

Award Number: R01NS091299

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: 06/01/2025

PERIOD OF PERFORMANCE END DATE: 05/31/2027

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer