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Mutant superoxide dismutase 1 (SOD1), a cause of amyotrophic lateral sclerosis, disrupts the recruitment of SMN, the spinal muscular atrophy protein to nuclear Cajal bodies.
- Source :
-
Human molecular genetics [Hum Mol Genet] 2012 Aug 01; Vol. 21 (15), pp. 3421-34. Date of Electronic Publication: 2012 May 11. - Publication Year :
- 2012
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Abstract
- Spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS) are among the most common motor neuron diseases to afflict the human population. A deficiency of the survival of motor neuron (SMN) protein causes SMA and is also reported to be an exacerbating factor in the development of ALS. However, pathways linking the two diseases have yet to be defined and it is not clear precisely how the pathology of ALS is aggravated by reduced SMN or whether mutant proteins underlying familial forms of ALS interfere with SMN-related biochemical pathways to exacerbate the neurodegenerative process. In this study, we show that mutant superoxide dismutase-1 (SOD1), a cause of familial ALS, profoundly alters the sub-cellular localization of the SMN protein, preventing the formation of nuclear 'gems' by disrupting the recruitment of the protein to Cajal bodies. Overexpressing the SMN protein in mutant SOD1 mice, a model of familial ALS, alleviates this phenomenon, most likely in a cell-autonomous manner, and significantly mitigates the loss of motor neurons in the spinal cord and in culture dishes. In the mice, the onset of the neuromuscular phenotype is delayed and motor function enhanced, suggestive of a therapeutic benefit for ALS patients treated with agents that augment the SMN protein. Nevertheless, this finding is tempered by an inability to prolong survival, a limitation most likely imposed by the inexorable denervation that characterizes ALS and eventually disrupts the neuromuscular synapses even in the presence of increased SMN.
- Subjects :
- Amyotrophic Lateral Sclerosis genetics
Amyotrophic Lateral Sclerosis metabolism
Animals
Disease Models, Animal
Mice
Mice, Knockout
Mice, Transgenic
Muscular Atrophy, Spinal metabolism
Superoxide Dismutase metabolism
Superoxide Dismutase-1
Survival of Motor Neuron 1 Protein genetics
Amyotrophic Lateral Sclerosis enzymology
Cell Nucleus metabolism
Muscular Atrophy, Spinal enzymology
Muscular Atrophy, Spinal genetics
Mutation
Superoxide Dismutase genetics
Survival of Motor Neuron 1 Protein metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1460-2083
- Volume :
- 21
- Issue :
- 15
- Database :
- MEDLINE
- Journal :
- Human molecular genetics
- Publication Type :
- Academic Journal
- Accession number :
- 22581780
- Full Text :
- https://doi.org/10.1093/hmg/dds174