Skeletal Muscle Pathology in Autosomal Recessive Cerebellar Ataxias: Insights from Marinesco–Sjögren Syndrome
Abstract
1. Introduction to ARCAs
2. Overview of Marinesco–Sjögren Syndrome
2.1. Genetic and Molecular Basis of MSS
2.2. Skeletal Muscle Histopathology in MSS
2.3. Pathophysiological Mechanisms
2.4. Animal Models and Translational Insights of MSS
3. Comparative Analysis of MSS with Other ARCAs or Myopathies
ARCAs Animal Models
4. Clinical and Therapeutic Implications
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
AAV | Adeno-associate virus |
ADCAs | Autosomal dominant cerebellar ataxias |
AOA1/2 | Oculomotor ataxia-apraxia type ½ |
ARCAs | Autosomal recessive cerebellar ataxias |
ATF6 | Activating transcription factor 6 |
A-T | Ataxia-telangiectasia |
AVED | Ataxia with vitamin E deficiency |
BCL2 | BCL2 Apoptosis regulator |
BiP/GRP78 | ER chaperone immunoglobulin binding protein |
BniP-h (Atcay) | Caytaxin |
CSA | Cross-sectional area |
COX | Cytochrome c oxidase |
DE | Differentially expressed (proteins) |
DMF | Dimethyl fumarate |
ER | Endoplasmic reticulum |
FRDA | Friedreich’s ataxia |
FXN | Frataxia |
HSV | Herpes simplex virus |
iPSCs | Induced pluripotent stem cells |
IRE-1 | Inositol-requiring enzyme 1 |
LC3 | Microtubule associated protein 1 light chain 3 Alpha (MAP1LC3A) |
MCK | Muscle creatine kinase |
MERRF | Myoclonus epilepsy with ragged-red fibers |
MIRAS | Mitochondrial recessive ataxia syndrome |
MRI | Magnetic resonance imaging |
MSS | Marinesco–Sjögren syndrome |
MT-CO2 | mtDNA variant in the cytochrome C oxidase II |
mtDNA | Mitochondrial DNA |
NEF | Nucleotide exchange factor |
ORP150/GRP170 | 150 kDa Oxygen-regulated protein |
PARP1 | Poly (ADP-Ribose) Polymerase 1 |
PERK | ER kinase |
PCr | Phosphocreatine recoveries |
PCs | Purkinje cells |
PKR | Protein kinase R |
Polg | DNA polymerase gamma |
p-eIF2α | Phospho-eukaryotic initiation factor 2α |
SCAR | Autosomal recessive spinocerebellar ataxia |
SIL1 | SIL1 nucleotide exchange factor |
SPG7 | Spastic paraplegic 7 |
SYNE1 | Spectron repeat containing nuclear envelope protein 1 |
UPR | Unfolded protein response |
WT | Wild-type |
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Observation | |||||||
---|---|---|---|---|---|---|---|
Fiber Size Variability | Fiber Type Grouping | Fatty Replacement | Mitochondrial Changes | Vacuolar Changes | Nuclear Changes | No Alterations | |
Ataxias with DNA repair defects | |||||||
A–T | - | - | - | - | - | - | - |
AOA1/2 | + [80] | - | - | - | - | - | + [81,82] |
Degenerative ataxias | |||||||
FRDA | - | + [55,56] | + [55,56] | + [55,56] | - | - | - |
MSS | ++ [12,21,23,24,26,27,28,30,32,33,34,35,36,37,38,39,40] | + [33,34,35,36,37] | ++ [21,24,27,30,32,34,35,37,38,39] | +++ [25,27,30,40] | +++ [12,23,25,26,28,30,31,32,34,35,36,37,38,39] | +++ [12,19,23,26,27,28,30,32,33,36,37,39] | - |
CoQ10 | - | - | - | - | - | - | + [61] |
ARCA-1 / SCAR8 | + [59] | - | + [59] | - | - | + [59] | - |
SCAR2 | + [88] | - | - | - | - | + [88] | - |
MIRAS | - | + [63,65] | - | ++ [62,63,64,65] | - | - | - |
SPG7 | + [68] | + [67,68] | - | ++ [67,68,69,70] | + [71] | - | + [72,73] |
Congenital ataxias | |||||||
Joubert | - | - | + [84] | + [83] | - | - | + [83] |
Cayman | - | - | - | - | - | - | - |
Metabolic ataxias | |||||||
AVED | + [85,86] | - | - | - | - | + [86] | - |
Wilson’s | - | - | - | - | - | - | + [87] |
Refsum’s | - | - | - | - | - | - | - |
Disease | Preclinical Model (Name-Age) | Observations | Reference |
---|---|---|---|
Degenerative ataxias | |||
MSS | Woozy mouse - 26 to 100 weeks of age | − Muscle atrophy − Variation in fiber size − Internalized nuclei − Rimmed vacuoles − Autophagic structures − Membrane-bound vacuolar structures − Swollen mitochondria | [26] |
MSS | Woozy mouse - 6 to 26 weeks of age | − Muscle atrophy − Autophagic vacuoles − Degenerating mitochondria − Degenerating nuclei | [43] |
MSS | Woozy mouse - 16 weeks of age | − Enlargements of the sarcoplasmic reticulum − Perinuclear autophagic vacuoles containing myelin-like membranous material | [44] |
MSS | Woozy mouse - 26 weeks of age | − Reduction in the size of NMJs | [25] |
MSS | Woozy mouse - 5 to 71 weeks of age | − Atrophic fibers − Autophagic vacuoles | [45] |
MSS | Sil1Gt mouse - 3 to 15 months of age | − Variable fiber size − Internalized nuclei − Fatty replacement − Degenerating nuclei surrounded by membranous-bound structure | [46] |
MSS | Morphant zebrafish - Embryos | − Markedly reduced normal patterns of birefringence − Disturbed myofibers formation | [47] |
FRDA | FXN-MCK mice - 2 to 10 weeks of age | − No histological, biochemical, or ultrastructural defects | [90] |
FRDA | Inducible FXN depletion (TG) mouse - 19 to 27 weeks of age | − Reduced growth of muscle mass, with smaller myofiber CSA, along with reduced translation of all proteins globally and no increase in autophagy | [93] |
FRDA | Conditioned FXN depleted - 5.5 to 21.5 weeks of age | − Coordination and muscle impairment | [96] |
MIRAS | polg knockout ENU zebrafish - Embryo and adults | − Altered fibers − Decrease in mitochondrial mass − Aberrant mitochondrial cristae | [101] |
Ataxias with impaired DNA repair mechanism | |||
A–T | ND | ||
AOA1/2 | ND | ||
Congenital ataxias | |||
Cayman ataxia | atcay knockdown zebrafish - adults | − Disrupted muscle development | [102] |
Joubert syndrome | ND | ||
Metabolic ataxias | |||
AVED | ND | ||
Wilson’s disease | ND | ||
Refsum’s disease | ND |
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Bellia, F.; Federici, L.; Gatta, V.; Calabrese, G.; Sallese, M. Skeletal Muscle Pathology in Autosomal Recessive Cerebellar Ataxias: Insights from Marinesco–Sjögren Syndrome. Int. J. Mol. Sci. 2025, 26, 6736. https://doi.org/10.3390/ijms26146736
Bellia F, Federici L, Gatta V, Calabrese G, Sallese M. Skeletal Muscle Pathology in Autosomal Recessive Cerebellar Ataxias: Insights from Marinesco–Sjögren Syndrome. International Journal of Molecular Sciences. 2025; 26(14):6736. https://doi.org/10.3390/ijms26146736
Chicago/Turabian StyleBellia, Fabio, Luca Federici, Valentina Gatta, Giuseppe Calabrese, and Michele Sallese. 2025. "Skeletal Muscle Pathology in Autosomal Recessive Cerebellar Ataxias: Insights from Marinesco–Sjögren Syndrome" International Journal of Molecular Sciences 26, no. 14: 6736. https://doi.org/10.3390/ijms26146736
APA StyleBellia, F., Federici, L., Gatta, V., Calabrese, G., & Sallese, M. (2025). Skeletal Muscle Pathology in Autosomal Recessive Cerebellar Ataxias: Insights from Marinesco–Sjögren Syndrome. International Journal of Molecular Sciences, 26(14), 6736. https://doi.org/10.3390/ijms26146736