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Defining the impact of Frataxin point mutations on Friedreich's ataxia pathogenesis

Award Number: R01NS121038
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: 03/01/2021
PERIOD OF PERFORMANCE END DATE: 02/28/2026

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Defining the impact of Frataxin point mutations on Friedreich's ataxia pathogenesis - Friedreich’s ataxia (FRDA) is an autosomal recessive neurodegenerative disease caused by reduced expression of the mitochondrial protein frataxin (FXN). Frataxin is translated as a 210 amino acid (aa) precursor (FXN-P) that is imported into the mitochondrial matrix where it undergoes sequential cleavage steps, producing a 168 aa intermediate (FXN-I) and the mature isoform of 129 aa (FXN-M). Frataxin participates in iron-sulfur cluster (ISC) biosynthesis in the mitochondria, and many of the overt FRDA phenotypes result from deficient activity of ISC- containing enzymes. Currently, there is no cure for this debilitating disease. Most FRDA patients are homozygous for large expansions of GAA triplet repeat sequences in intron 1 of the FXN gene, while a subset of patients are compound heterozygotes with an expanded GAA repeat tract in one FXN allele and a missense or nonsense mutation in the other. Homozygous and compound heterozygous mutant genotypes both result in reduced levels of FXN-M protein when compared with healthy controls. The most prevalent missense mutation changes a glycine to valine at position 130 (G130V). FRDA G130V patients exhibit different clinical features than patients harboring homozygous GAA expansions, including lower limb spasticity rather than ataxia, preserved sensory responses, spared speech and upper limb functions, and slower disease progression. Paradoxically, substantially less FXN-M protein is detectable in G130V patient samples than in patient samples harboring two expanded alleles. Our preliminary data revealed that normal mitochondrial maturation processing of the FXN protein is perturbed by the G130V mutation, suggesting functional importance of an intermediate isoform (G130V-I). We hypothesize that the G130V mutation impairs FXN mitochondrial maturation processing and/or destabilizes the mature isoform. The unprocessed FXN-G130V-I isoform is functional and partially compensates for the substantial reduction of FXN-M, thus slowing disease progression and contributing to the distinct symptoms of FRDA G130V patients. To address these hypotheses, we will use novel cellular and mouse models of FRDA G130V. First, we will define the structural and functional properties of the FXN-G130V-I isoform to test whether this mutation confers a change of function that contributes to the atypical clinical presentation of FRDA G130V patients. Subsequently, we will determine mechanisms governing steady state levels and maturation processing of FXN-G130V in iPSC-derived cortical and sensory neurons. Finally, using FRDA patient-derived neuronal models as well as our novel Fxn G127V mouse model, we will define molecular mechanisms underlying the unique clinical presentation of FRDA G130V patients. Results of the proposed studies will have a broad impact on therapy development for all FRDA patients.


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 = $369,000 )
2025	2025	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	2/14/2025	NON-COMPETING CONTINUATION	$369,000
														Subtotal = $369,000

Issue Date FY: 2024 ( Subtotal = $397,700 )
2024	2024	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	2/8/2024	NON-COMPETING CONTINUATION	$369,000
2024	2024	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	5/3/2024	NON-COMPETING CONTINUATION	$28,700
														Subtotal = $397,700

Issue Date FY: 2023 ( Subtotal = $410,000 )
2023	2023	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	2/27/2023	NON-COMPETING CONTINUATION	$410,000
														Subtotal = $410,000

Issue Date FY: 2022 ( Subtotal = $410,000 )
2022	2022	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	004	2	7/22/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$315,095
2022	2022	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	2	3/21/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$999
2022	2022	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	3/14/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$410,999
2022	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	3/11/2022	NEW	$0
2022	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	1	7/22/2022	NEW	-$315,095
														Subtotal = $410,000

Issue Date FY: 2021 ( Subtotal = $371,250 )
2021	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	2/15/2021	NEW	$371,250
														Subtotal = $371,250

Grand Total All Awards = $1,957,950

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Defining the impact of Frataxin point mutations on Friedreich's ataxia pathogenesis

Award Number: R01NS121038

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: 03/01/2021

PERIOD OF PERFORMANCE END DATE: 02/28/2026

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