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Dysregulation of inhibitory synapse by poly-GR in C9ORF72-ALS/FTD

Award Number: R21AG072078
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2021
PERIOD OF PERFORMANCE END DATE: 04/30/2024

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Dysregulation of inhibitory synapse by poly-GR in C9ORF72-ALS/FTD - The goal of the project is to understand the dysregulation of inhibitory synapse caused by poly-GR in C9ORF72-linked amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD). Hexanucleotide repeat expansion in the C9ORF72 gene is the most common genetic cause of both ALS and FTD. One potential pathogenic mechanism is the aberrant accumulation of dipeptide repeat (DPR) proteins produced by repeat-associated non-AUG (RAN) translation in all six reading frames (poly-GA, poly-GR, poly-PA, poly-PR and poly-PG) of both sense and antisense RNAs. Lines of evidence indicate that some forms of the DPR proteins, particularly GR and PR, can induce dysregulation of several molecular pathways, including stress granule dysfunction, nucleocytoplasmic transport defects, altered ER homeostasis, et al. How these molecular deficits influence neuronal functions remains understudied. Accumulating evidence indicated that changes of synapse density and function occurs prior to significant neuronal death in neurodegenerative diseases. The development of hyperexcitability is a well-known phenomenon. One plausible mechanism is the alterations in the ratio of excitatory to inhibitory activity (E/I imbalance). Our preliminary data identified specific reduction of gephyrin clustering, a scaffold protein essential for inhibitory synapse formation and function, in C9ORF72-ALS/FTD patient iPSC-neurons and in primary neurons with poly-GR expression. We now propose to characterize the structure and electrophysiological dysfunction of the inhibitory synapse, and to decipher the molecular mechanism how poly-GR causes such defects by combining different –omics techniques with molecular and cellular approaches. We aim to identify GR-interacting proteins in neurons using the proximity-labeling proteomics and GR-induced transcriptomic changes by high-throughput sequencing, which will reveal candidate genes/pathways for further mechanistic study of their contribution to GR-mediated synaptic dysregulation. This project makes an important first step toward understanding the molecular mechanisms of neuronal dysfunction in ALS and FTD patients. The molecular insights resulting from this study will help understanding the etiology of the disease and developing novel therapeutic targets.


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 = -$73 )
2024	2021	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Aging Research	000	1	9/3/2024	NEW	-$73
														Subtotal = -$73

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Aging Research	000	1	3/29/2023	NEW	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $450,313 )
2021	2021	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Aging Research	000	1	4/21/2021	NEW	$450,313
														Subtotal = $450,313

Grand Total All Awards = $450,240

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Dysregulation of inhibitory synapse by poly-GR in C9ORF72-ALS/FTD

Award Number: R21AG072078

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/01/2021

PERIOD OF PERFORMANCE END DATE: 04/30/2024

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