PXD044286

PXD044286 is an original dataset announced via ProteomeXchange.

Title	Multi-level profiling unravels mitochondrial dysfunction in Myotonic Dystrophy type 2
Description	Myotonic Dystrophy type 2 (DM2) is an autosomal-dominant, multisystemic disease with a core manifestation of proximal muscle weakness, muscle atrophy, myotonia, and myalgia. The disease-causing CCTG tetranucleotide expansion within the CNBP gene on chromosome 3 leads to an RNA-dominated spliceopathy which is currently untreatable. Research exploring the pathophysiological mechanisms in Myotonic Dystrophy Type 1 resulted in new insights into disease mechanisms and identified mitochondrial dysfunction as promising therapeutic target. It remains unclear whether similar mechanisms underlie DM2 and, if so, whether these might also serve as potential therapeutic targets. In this cross-sectional study, we studied DM2 skeletal muscle biopsy specimens on proteomic, molecular, and morphological including ultrastructural levels in two separate patient cohorts consisting of 8 (explorative cohort) and 40 (confirmatory cohort) patients. Seven muscle biopsy specimens obtained from four female and three male DM2 patients underwent proteomic analysis. We performed immunoblotting of respiratory chain complexes, mitochondrial DNA copy number determination and long-range PCR (LR-PCR) to study mitochondrial deletions on six biopsies. Forty-eight biopsy samples were studied by light and electron microscopy. Proteomic analysis revealed a downregulation of essential mitochondrial proteins, namely of subunits of respiratory chain complexes I, III, and IV (e.g. mt-CO1, mt-ND1, mt-CYB, NDUFB6) and associated translation factors (TACO1). Light microscopy showed an age-inappropriate amount of COX-deficient fibers in most biopsy specimens. Electron microscopy revealed widespread ultrastructural mitochondrial abnormalities including dysmorphic mitochondria with paracrystalline inclusions. Immunoblotting and LR-PCR did not reveal significant differences between patients and controls, while mtDNA-copy number measurement revealed a reduction of mtDNA-copy numbers in the patient group compared to controls. This first multi-level study of DM2 unravels thus far undescribed functional and structural mitochondrial abnormalities. While the molecular link between the tetranucleotide expansion, and mitochondrial dysfunction needs to be further elucidated, these findings may provide an additional route for treatment strategies for DM2.
HostingRepository	PRIDE
AnnounceDate	2024-01-26
AnnouncementXML	Submission_2024-01-26_09:03:58.583.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Andreas Hentschel
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	iodoacetamide derivatized residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2023-08-02 00:14:00	ID requested
⏵ 1	2024-01-26 09:03:59	announced

Kleefeld F, Horvath R, Pinal-Fernandez I, Mammen AL, Casal-Dominguez M, Hathazi D, Melchert S, Hahn K, Sickmann A, Muselmann-Genschow C, Hentschel A, Preu, ß, e C, Roos A, Schoser B, Stenzel W, Multi-level profiling unravels mitochondrial dysfunction in myotonic dystrophy type 2. Acta Neuropathol, 147(1):19(2024) [pubmed]

10.1007/s00401-023-02673-y;

submitter keyword: Myotonic Dystrophy Type 2, repeat expansion disease, Proximal Myotonic Myopathy, mitochondrial dysfunction

Andreas Hentschel
contact affiliation	Proteomics, Biomarker, Leibniz-Institut für analytische Wissenschaften -ISAS - e.V., Germany
contact email	andreas.hentschel@isas.de
lab head
Andreas Hentschel
contact affiliation	Leibniz Institut für Analytische Wissenschaften
contact email	andreas.hentschel@isas.de
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD044286
     1. Label: PRIDE project
     2. Name: Multi-level profiling unravels mitochondrial dysfunction in Myotonic Dystrophy type 2