PXD042201

PXD042201 is an original dataset announced via ProteomeXchange.

Title	Identifying secondary processes implicated in nemaline myopathy pathophysiology
Description	Nemaline myopathy (NM) is a genetically and clinically heterogeneous disease that is diagnosed based on the presence of nemaline rods on skeletal muscle biopsy. While NM has typically been classified by causative genes, disease severity or prognosis cannot be predicted well. The common pathological endpoint of nemaline rods (despite diverse genetic causes) and an unexplained range of muscle weakness suggests that shared secondary processes contributed to the pathogenesis of NM. We speculated that these processes could be identified through a proteome wide interrogation utilizing a mouse model of severe NM in combination with pathway validation and structural/functional analyses. A proteomic analysis was performed using skeletal muscle tissue from the Neb cKO, KI.Acta1H40Y, and TgACTA1D286G mouse models of nemaline myopathy as compared to their respective wild-type counterparts (Neb WT, WT.Acta1H40Y, and C57) to identify pathophysiologically relevant biological processes that might impact disease severity or provide new treatment targets. Downstream analyses utilizing Scaffold, RStudio, and Ingenuity Pathway Analysis identified mitochondrial dysfunction and stress-related signaling as being enriched in NM mouse datasets. Pathway validation revealed that proteins in mitochondrial and stress-related signaling pathways aggregated in NM muscle in a severity dependent manner and an increase in protein content was generally associated with more severe disease. Structural and functional mitochondrial analyses revealed that mitochondrial dysfunction also grades with disease severity. RCI measured by respirometry, ATP/ADP/phosphate content, and mitochondrial transmembrane potential were affected in a severity dependent manner with the Neb cKOs being the most abnormal, KI.Acta1H40Y being mildly affected, and the TgACTA1D286G being minimally affected. These studies identify mitochondrial dysfunction as a secondary process impacting disease severity in NM.
HostingRepository	PRIDE
AnnounceDate	2025-05-06
AnnouncementXML	Submission_2025-05-06_10:35:10.924.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Rebecca Slick
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	No PTMs are included in the dataset
Instrument	Bruker Daltonics timsTOF series; Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2023-05-12 21:07:45	ID requested
⏵ 1	2025-05-06 10:35:11	announced

Tinklenberg JA, Slick RA, Sutton J, Zhang L, Meng H, Beatka MJ, Vanden Avond M, Prom MJ, Ott E, Montanaro F, Heisner J, Toro R, Hardeman EC, Geurts AM, Stowe DF, Hill RB, Lawlor MW, Different Mouse Models of Nemaline Myopathy Harboring Acta1 Mutations Display Differing Abnormalities Related to Mitochondrial Biology. Am J Pathol, 193(10):1548-1567(2023) [pubmed]

10.1016/j.ajpath.2023.06.008;

submitter keyword: nemaline myopathy, Neb cKO, Acta1

Michael William Lawlor
contact affiliation	Medical College of Wisconsin
contact email	mlawlor@mcw.edu
lab head
Rebecca Slick
contact affiliation	University of Minnesota
contact email	raslick@mcw.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD042201
     1. Label: PRIDE project
     2. Name: Identifying secondary processes implicated in nemaline myopathy pathophysiology