Molecular signatures of inherited and acquired sporadic late onset nemaline myopathies

Acta Neuropathologica Communications

Research

Aneesha Dasgupta¹  Jason D. Doles¹  Akhilesh Pandey²  Margherita Milone³  Stefan Nicolau⁴  Surendra Dasari⁵  M. Cristine Charlesworth⁶  Kenneth L. Johnson⁶ 

[1] Department of Biochemistry and Molecular Biology, Mayo Clinic, 55905, Rochester, MN, USA;Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, 46202, Indianapolis, IN, USA;Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, 46202, Indianapolis, IN, USA;Department of Laboratory Medicine and Pathology, Mayo Clinic, 55905, Rochester, MN, USA;Manipal Academy of Higher Education (MAHE), 576104, Manipal, Karnataka, India;Department of Neurology, Mayo Clinic, 200 First St. SW, 55905, Rochester, MN, USA;Department of Neurology, Mayo Clinic, 200 First St. SW, 55905, Rochester, MN, USA;Center for Gene Therapy, Nationwide Children’s Hospital, 43205, Columbus, OH, USA;Department of Quantitative Health Sciences, Mayo Clinic, 55905, Rochester, MN, USA;Proteomics Core, Medical Genomics Facility, Mayo Clinic, 55905, Rochester, MN, USA;

关键词: Nemaline myopathy;    NEB;    ACTA1;    Histology;    Proteomics;    Transcriptomics;    RNA-seq;   

DOI  :  10.1186/s40478-023-01518-9

 received in 2022-12-20, accepted in 2023-01-18,  发布年份 2023

来源: Springer

【 摘 要 】

Acquired sporadic late onset nemaline myopathy (SLONM) and inherited nemaline myopathy (iNM) both feature accumulation of nemaline rods in muscle fibers. Unlike iNM, SLONM is amenable to therapy. The distinction between these disorders is therefore crucial when the diagnosis remains ambiguous after initial investigations. We sought to identify biomarkers facilitating this distinction and to investigate the pathophysiology of nemaline rod formation in these different disorders. Twenty-two muscle samples from patients affected by SLONM or iNM underwent quantitative histological analysis, laser capture microdissection for proteomic analysis of nemaline rod areas and rod-free areas, and transcriptomic analysis. In all iNM samples, nemaline rods were found in subsarcolemmal or central aggregates, whereas they were diffusely distributed within muscle fibers in most SLONM samples. In SLONM, muscle fibers harboring nemaline rods were smaller than those without rods. Necrotic fibers, increased endomysial connective tissue, and atrophic fibers filled with nemaline rods were more common in SLONM. Proteomic analysis detected differentially expressed proteins between nemaline rod areas and rod-free areas, as well as between SLONM and iNM. These differentially expressed proteins implicated immune, structural, metabolic, and cellular processes in disease pathophysiology. Notably, immunoglobulin overexpression with accumulation in nemaline rod areas was detected in SLONM. Transcriptomic analysis corroborated proteomic findings and further revealed substantial gene expression differences between SLONM and iNM. Overall, we identified unique pathological and molecular signatures associated with SLONM and iNM, suggesting distinct underlying pathophysiological mechanisms. These findings represent a step towards enhanced diagnostic tools and towards development of treatments for SLONM.

【 授权许可】

CC BY   
© The Author(s) 2023

【 图 表 】

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