Dataset Information

Skeletal muscle proteomics underpin multifaceted mitochondrial dysfunction in Friedreich´s Ataxia

ABSTRACT: Friedreich´s Ataxia (FRDA) is a severe neuromuscular disorder caused by a deficiency of the mitochondrial protein frataxin. While some aspects of FRDA pathology are developmental, the causes underlying the steady progression are unclear. The inaccessibility of key affected tissues to sampling is a main hurdle. Skeletal muscle displays a disease phenotype and may be sampled in vivo to address open questions on FRDA pathophysiology. We performed a mass spectrometry (MS)-based proteomics analysis in gastrocnemius skeletal muscle biopsies from genetically confirmed FRDA patients (n=5) and controls. Our data corroborate a predominant mitochondrial biosignature of FRDA, which extends beyond a mere oxidative phosphorylation failure. Skeletal muscle proteomics highlighted a derangement of mitochondrial architecture and maintenance pathways and an adaptative metabolic shift of contractile proteins. The present findings are relevant for the design of future therapeutic strategies and highlight the value of skeletal muscle -omics as disease state readout in FRDA.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Gastrocnemius

DISEASE(S): Friedreich Ataxia

SUBMITTER: Klaus Faserl

LAB HEAD: Klaus Faserl

PROVIDER: PXD044554 | Pride | 2023-12-04

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	Friedreichs_Ataxia_proteomics_study.msf	Msf
	Friedreichs_Ataxia_proteomics_study.pdResult	Other
	TMT-Pool.raw	Raw
	TMT-Pool10-25.raw	Raw
	TMT-Pool11-26.raw	Raw

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Publications

Skeletal muscle proteome analysis underpins multifaceted mitochondrial dysfunction in Friedreich's ataxia.

Indelicato Elisabetta E Faserl Klaus K Amprosi Matthias M Nachbauer Wolfgang W Schneider Rainer R Wanschitz Julia J Sarg Bettina B Boesch Sylvia S

Frontiers in neuroscience 20231031

Friedreich's ataxia (FRDA) is a severe multisystemic disorder caused by a deficiency of the mitochondrial protein frataxin. While some aspects of FRDA pathology are developmental, the causes underlying the steady progression are unclear. The inaccessibility of key affected tissues to sampling is a main hurdle. Skeletal muscle displays a disease phenotype and may be sampled <i>in vivo</i> to address open questions on FRDA pathophysiology. Thus, we performed a quantitative mass spectrometry-based ...[more]

PMID: 38027498

Similar Datasets

Project description:Background: Friedreich ataxia, an autosomal recessive neurodegenerative and cardiac disease, is caused by abnormally low levels of frataxin, an essential mitochondrial protein. All Friedreich ataxia patients carry a GAA/TTC repeat expansion in the first intron of the frataxin gene, either in the homozygous state or in compound heterozygosity with other loss-of-function mutations. The GAA expansion inhibits frataxin expression through a heterochromatin-mediated repression mechanism. Histone modifications that are characteristic of silenced genes in heterochromatic regions occur at expanded alleles in cells from Friedreich ataxia patients, including increased trimethylation of histone H3 at lysine 9 and hypoacetylation of histones H3 and H4. Methodology/Principal Findings: By chromatin immunoprecipitation, we detected the same heterochromatin marks in homozygous mice carrying a (GAA)230 repeat in the first intron of the mouse frataxin gene (KIKI mice). These animals have decreased frataxin levels and, by microarray analysis, show significant gene expression changes in several tissues. We treated KIKI mice with a novel histone deacetylase inhibitor, compound 106, which substantially increases frataxin mRNA levels in cells from Friedreich ataxia individuals. Treatment increased histone H3 and H4 acetylation in chromatin near the GAA repeat and restored wild-type frataxin levels in the nervous system and heart, as determined by quantitative RT-PCR and semiquantitative western blot analysis. No toxicity was observed. Furthermore, most of the differentially expressed genes in KIKI mice reverted towards wild-type levels. Conclusions/Significance: Lack of acute toxicity, normalization of frataxin levels and of the transcription profile changes resulting from frataxin deficiency provide strong support to a possible efficacy of this or related compounds in reverting the pathological process in Friedreich ataxia, a so far incurable neurodegenerative disease. Keywords: drug response