Official websites use .gov

A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS

A lock ( 🔒 ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

Need Help

Modeling DYT1 Dystonia in Patient-derived Neurons

Award Number: R56NS133252
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: 09/01/2023
PERIOD OF PERFORMANCE END DATE: 08/31/2025

Group Awards By:

View Award Description

Modeling DYT1 Dystonia in Patient-derived Neurons - TITLE Modeling DYT1 Dystonia in Patient-derived Neurons PROJECT SUMMARY The overall goal of this project is to develop novel cellular systems for dystonia research and determine the molecular pathogenesis of DYT1 dystonia using patient-derived neurons. Dystonia is the third most common movement disorder and the pathological mechanisms responsible for dystonia remain largely unknown 1-5. Current therapies are largely symptom-based and only partially satisfactory 6,7. DYT1 dystonia, which represents the most frequent and severe form of hereditary primary dystonia, provides an excellent model for studies that aim to understand the pathogenesis of this disease 8,9. Typical DYT1 dystonia is caused by a heterozygous GAG deletion in the TOR1A gene (ΔE). Even though animal models provide insights into disease mechanisms, significant species-dependent differences exist because animals with identical heterozygous mutation (ΔE) fail to show the pathology seen in human patients 10. In addition, the limited access to patient neurons greatly impedes the progress of research in dystonia. In a breakthrough, we have developed a novel cellular system for modeling DYT1 dystonia with patient-specific neurons 11,12. These human neurons retain the heterozygous TOR1A mutation and recapitulate disease-dependent cellular deficits. The most unexpected finding is that nuclear lamina protein LMNB1 was dysregulated at expression and subcellular distribution. Interestingly, downregulation of LMNB1 can largely ameliorate all the cellular deficits in DYT1 neurons 11. These results demonstrate the high value of disease modeling using human patient-derived neurons and indicate that dysregulation of nuclear LMNB1 may constitute a major molecular mechanism underlying DYT1 pathology. How does dysregulated LMNB1 contribute to the pathogenesis of dystonia? What other proteins and genes could be disrupted by ΔE? Answers to these questions are critical in understanding the pathophysiology of DYT1 dystonia. We hypothesize that the dysregulation of nuclear LMNB1 is the major contributor to the cellular deficits, and the mislocalized LMNB1 in the cytoplasm could trap factors in critical signaling pathways and lead to widescale cellular dysfunction. We will use patient-derived neurons to test this hypothesis and address pertaining questions via three specific aims. Aim 1 is to determine how dysregulated LMNB1 contributes to the cellular dysfunction in DYT1 neurons, including examination of nuclear morphology using TEM and immunogold labeling, and identification of mislocalized LMNB1-interacting proteins. In Aim 2, we will identify ΔE-disrupted factors using proteomic studies and examine the abnormal protein-protein interactions using the combination of Artificial Intelligence (AI)-based structural prediction and approaches in molecular biology and biochemistry. In Aim 3, we will identify dysregulated genes using transcriptomic study and examine the functional alterations via electrophysiology analysis and in vitro neuromuscular junction formation assay. The successful completion of these Aims will allow us to gain a more in-depth understanding of the pathogenesis of dystonia.


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 = $0 )
2026	2023	LOUISIANA STATE UNIVERSITY	1501 KINGS HWY	SHREVEPORT	LA	71103	CADDO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	3/2/2026	NEW	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $365,000 )
2023	2023	LOUISIANA STATE UNIVERSITY	1501 KINGS HWY	SHREVEPORT	LA	71103	CADDO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	8/24/2023	NEW	$365,000
														Subtotal = $365,000

Grand Total All Awards = $365,000

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Modeling DYT1 Dystonia in Patient-derived Neurons

Award Number: R56NS133252

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: 09/01/2023

PERIOD OF PERFORMANCE END DATE: 08/31/2025

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer