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Nuclear pore pathology underlying multisystem proteinopathy type 3-related inclusion body myopathy. | LitMetric

AI Article Synopsis

  • Multisystem proteinopathy type 3 (MSP3) is a hereditary condition linked to a mutation in the hnRNPA1 gene affecting muscles, bones, and the nervous system; this study focused on understanding how this mutation impacts skeletal muscle in hereditary inclusion body myopathy (hIBM), a key MSP3 subtype.* -
  • Researchers conducted RNA sequencing and histopathological analyses of skeletal muscles with a specific hnRNPA1 mutation, discovering abnormal splicing events and mislocalized nucleoporins that suggest disrupted nuclear pore complex and nucleocytoplasmic transport pathways.* -
  • The findings indicate that the altered expression of nucleoporins in muscle tissues from both HNRNPA1-mutated and unlinked hIBM

Article Abstract

Objective: Multisystem proteinopathy type 3 (MSP3) is an inherited, pleiotropic degenerative disorder caused by a mutation in heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1), which can affect the muscle, bone, and/or nervous system. This study aimed to determine detailed histopathological features and transcriptomic profile of HNRNPA1-mutated skeletal muscles to reveal the core pathomechanism of hereditary inclusion body myopathy (hIBM), a predominant phenotype of MSP3.

Methods: Histopathological analyses and RNA sequencing of HNRNPA1-mutated skeletal muscles harboring a c.940G > A (p.D314N) mutation (NM_031157) were performed, and the results were compared with those of HNRNPA1-unlinked hIBM and control muscle tissues.

Results: RNA sequencing revealed aberrant alternative splicing events that predominantly occurred in myofibril components and mitochondrial respiratory complex. Enrichment analyses identified the nuclear pore complex (NPC) and nucleocytoplasmic transport as suppressed pathways. These two pathways were linked by the hub genes NUP50, NUP98, NUP153, NUP205, and RanBP2. In immunohistochemistry, these nucleoporin proteins (NUPs) were mislocalized to the cytoplasm and aggregated mostly with TAR DNA-binding protein 43 kDa and, to a lesser extent, with hnRNPA1. Based on ultrastructural observation, irregularly shaped myonuclei with deep invaginations were frequently observed in atrophic fibers, consistent with the disorganization of NPCs. Additionally, regarding the expression profiles of overall NUPs, reduced expression of NUP98, NUP153, and RanBP2 was shared with HNRNPA1-unlinked hIBMs.

Interpretation: The shared subset of altered NUPs in amyotrophic lateral sclerosis (ALS), as demonstrated in prior research, HNRNPA1-mutated, and HNRNPA1-unlinked hIBM muscle tissues may provide evidence regarding the underlying common nuclear pore pathology of hIBM, ALS, and MSP.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10963302PMC
http://dx.doi.org/10.1002/acn3.51977DOI Listing

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