Abstract:
:Spinal muscular atrophy (SMA) is a common pediatric neuromuscular disorder caused by insufficient levels of the survival of motor neuron (SMN) protein. Studies involving SMA patients and animal models expressing the human SMN2 gene have yielded relatively little information about the earliest cellular consequences of reduced SMN protein. In this study, we have used severe- and mild-SMN2 expressing mouse models of SMA as well as material from human patients to understand the initial stages of neurodegeneration in the human disease. We show that the earliest structural defects appear distally and involve the neuromuscular synapse. Insufficient SMN protein arrests the post-natal development of the neuromuscular junction (NMJ), impairing the maturation of acetylcholine receptor (AChR) clusters into 'pretzels'. Pre-synaptic defects include poor terminal arborization and intermediate filament aggregates which may serve as a useful biomarker of the disease. These defects are reflected in functional deficits at the NMJ characterized by intermittent neurotransmission failures. We suggest that SMA might best be described as a NMJ synaptopathy and that one promising means of treating it could involve maintaining function at the NMJ.
journal_name
Hum Mol Genetjournal_title
Human molecular geneticsauthors
Kariya S,Park GH,Maeno-Hikichi Y,Leykekhman O,Lutz C,Arkovitz MS,Landmesser LT,Monani URdoi
10.1093/hmg/ddn156subject
Has Abstractpub_date
2008-08-15 00:00:00pages
2552-69issue
16eissn
0964-6906issn
1460-2083pii
ddn156journal_volume
17pub_type
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