Skeletal muscle cell protein dysregulation highlights the pathogenesis mechanism of myopathy-associated p97/VCP R155H mutations
p97/VCP, a hexametric member of the AAA-ATPase superfamily, has been associated with a wide range of cellular protein pathways, such as proteasomal degradation, the unfolding of polyubiquitinated proteins, and autophagosome maturation. Autosomal dominant p97/VCP mutations cause a rare hereditary mul...
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| Format: | Article |
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Frontiers Media S.A.
2023-08-01
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| Series: | Frontiers in Neurology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fneur.2023.1211635/full |
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| author | Anna Luzzi Feng Wang Shan Li Michelina Iacovino Michelina Iacovino Tsui-Fen Chou Tsui-Fen Chou |
| author_facet | Anna Luzzi Feng Wang Shan Li Michelina Iacovino Michelina Iacovino Tsui-Fen Chou Tsui-Fen Chou |
| author_sort | Anna Luzzi |
| collection | DOAJ |
| description | p97/VCP, a hexametric member of the AAA-ATPase superfamily, has been associated with a wide range of cellular protein pathways, such as proteasomal degradation, the unfolding of polyubiquitinated proteins, and autophagosome maturation. Autosomal dominant p97/VCP mutations cause a rare hereditary multisystem disorder called IBMPFD/ALS (Inclusion Body Myopathy with Paget’s Disease and Frontotemporal Dementia/Amyotrophic Lateral Sclerosis), characterized by progressive weakness and subsequent atrophy of skeletal muscles, and impacting bones and brains, such as Parkinson’s disease, Lewy body disease, Huntington’s disease, and amyotrophic lateral ALS. Among all disease-causing mutations, Arginine 155 to Histidine (R155H/+) was reported to be the most common one, affecting over 50% of IBMPFD patients, resulting in disabling muscle weakness, which might eventually be life-threatening due to cardiac and respiratory muscle involvement. Induced pluripotent stem cells (iPSCs) offer an unlimited resource of cells to study pathology’s underlying molecular mechanism, perform drug screening, and investigate regeneration. Using R155H/+ patients’ fibroblasts, we generated IPS cells and corrected the mutation (Histidine to Arginine, H155R) to generate isogenic control cells before differentiating them into myotubes. The further proteomic analysis allowed us to identify differentially expressed proteins associated with the R155H mutation. Our results showed that R155H/+ cells were associated with dysregulated expression of several proteins involved in skeletal muscle function, cytoskeleton organization, cell signaling, intracellular organelles organization and function, cell junction, and cell adhesion. Our findings provide molecular evidence of dysfunctional protein expression in R155H/+ myotubes and offer new therapeutic targets for treating IBMPFD/ALS. |
| first_indexed | 2024-03-12T17:44:07Z |
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| id | doaj.art-e10dd17d0c124bd1a26e0524d5b1de36 |
| institution | Directory Open Access Journal |
| issn | 1664-2295 |
| language | English |
| last_indexed | 2024-03-12T17:44:07Z |
| publishDate | 2023-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Neurology |
| spelling | doaj.art-e10dd17d0c124bd1a26e0524d5b1de362023-08-03T23:03:06ZengFrontiers Media S.A.Frontiers in Neurology1664-22952023-08-011410.3389/fneur.2023.12116351211635Skeletal muscle cell protein dysregulation highlights the pathogenesis mechanism of myopathy-associated p97/VCP R155H mutationsAnna Luzzi0Feng Wang1Shan Li2Michelina Iacovino3Michelina Iacovino4Tsui-Fen Chou5Tsui-Fen Chou6The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, United StatesThe Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, United StatesThe Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, United StatesThe Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, United StatesDepartment of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, CA, United StatesThe Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, United StatesDivision of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, United Statesp97/VCP, a hexametric member of the AAA-ATPase superfamily, has been associated with a wide range of cellular protein pathways, such as proteasomal degradation, the unfolding of polyubiquitinated proteins, and autophagosome maturation. Autosomal dominant p97/VCP mutations cause a rare hereditary multisystem disorder called IBMPFD/ALS (Inclusion Body Myopathy with Paget’s Disease and Frontotemporal Dementia/Amyotrophic Lateral Sclerosis), characterized by progressive weakness and subsequent atrophy of skeletal muscles, and impacting bones and brains, such as Parkinson’s disease, Lewy body disease, Huntington’s disease, and amyotrophic lateral ALS. Among all disease-causing mutations, Arginine 155 to Histidine (R155H/+) was reported to be the most common one, affecting over 50% of IBMPFD patients, resulting in disabling muscle weakness, which might eventually be life-threatening due to cardiac and respiratory muscle involvement. Induced pluripotent stem cells (iPSCs) offer an unlimited resource of cells to study pathology’s underlying molecular mechanism, perform drug screening, and investigate regeneration. Using R155H/+ patients’ fibroblasts, we generated IPS cells and corrected the mutation (Histidine to Arginine, H155R) to generate isogenic control cells before differentiating them into myotubes. The further proteomic analysis allowed us to identify differentially expressed proteins associated with the R155H mutation. Our results showed that R155H/+ cells were associated with dysregulated expression of several proteins involved in skeletal muscle function, cytoskeleton organization, cell signaling, intracellular organelles organization and function, cell junction, and cell adhesion. Our findings provide molecular evidence of dysfunctional protein expression in R155H/+ myotubes and offer new therapeutic targets for treating IBMPFD/ALS.https://www.frontiersin.org/articles/10.3389/fneur.2023.1211635/fullVCP/p97IBMPFD/ALSiPSCsskeletal musclemyopathyR155H mutation |
| spellingShingle | Anna Luzzi Feng Wang Shan Li Michelina Iacovino Michelina Iacovino Tsui-Fen Chou Tsui-Fen Chou Skeletal muscle cell protein dysregulation highlights the pathogenesis mechanism of myopathy-associated p97/VCP R155H mutations Frontiers in Neurology VCP/p97 IBMPFD/ALS iPSCs skeletal muscle myopathy R155H mutation |
| title | Skeletal muscle cell protein dysregulation highlights the pathogenesis mechanism of myopathy-associated p97/VCP R155H mutations |
| title_full | Skeletal muscle cell protein dysregulation highlights the pathogenesis mechanism of myopathy-associated p97/VCP R155H mutations |
| title_fullStr | Skeletal muscle cell protein dysregulation highlights the pathogenesis mechanism of myopathy-associated p97/VCP R155H mutations |
| title_full_unstemmed | Skeletal muscle cell protein dysregulation highlights the pathogenesis mechanism of myopathy-associated p97/VCP R155H mutations |
| title_short | Skeletal muscle cell protein dysregulation highlights the pathogenesis mechanism of myopathy-associated p97/VCP R155H mutations |
| title_sort | skeletal muscle cell protein dysregulation highlights the pathogenesis mechanism of myopathy associated p97 vcp r155h mutations |
| topic | VCP/p97 IBMPFD/ALS iPSCs skeletal muscle myopathy R155H mutation |
| url | https://www.frontiersin.org/articles/10.3389/fneur.2023.1211635/full |
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