Resumen
Dosage of the survival motor neuron (SMN) protein has been directly correlated with the severity of disease in patients diagnosed with spinal muscular atrophy (SMA). It is also clear that SMA is a neurodegenerative disorder characterized by the degeneration of the α-motor neurons in the anterior horn of the spinal cord and atrophy of the associated skeletal muscle. What is more controversial is whether it is neuronal and/or muscle-cell- autonomous defects that are responsible for the disease per se. Although motor neuron degeneration is generally accepted as the primary event in SMA, intrinsic muscle defects in this disease have not been ruled out. To gain a better understanding of the influence of SMN protein dosage in muscle, we have generated a hypomorphic series of myoblast (C2C12) stable cell lines with variable Smn knockdown. We show that depletion of Smn in these cells resulted in a decrease in the number of nuclear 'gems' (gemini of coiled bodies), reduced proliferation with no increase in cell death, defects in myoblast fusion, and malformed myotubes. Importantly, the severity of these abnormalities is directly correlated with the decrease in Smn dosage. Taken together, our work supports the view that there is an intrinsic defect in skeletal muscle cells of SMA patients and that this defect contributes to the overall pathogenesis in this devastating disease.
Idioma original | English |
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Páginas (desde-hasta) | 49-61 |
Número de páginas | 13 |
Publicación | Experimental Cell Research |
Volumen | 311 |
N.º | 1 |
DOI | |
Estado | Published - nov. 15 2005 |
Publicado de forma externa | Sí |
Nota bibliográfica
Funding Information:We are grateful to Dennis Bulman for critical reading of the manuscript and the rest of the Kothary laboratory for helpful discussions. We also thank Dr. Robin Parks for the sh_LacZ_1348 construct used in these studies and the Jesse's Journey Foundation for Gene and Cell Therapy for their generous support of our research program. This project was funded by a grant from the Canadian Institutes of Health Research (CIHR) to R.K. D.S. is a recipient of an Ontario Graduate Scholarship, and P.D.C. is supported by a Fellowship from the CIHR.
ASJC Scopus Subject Areas
- Cell Biology