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Survival of motor neurons

Survival of motor neurons - Neurotoxicity Research 2008 VOL...

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Progressive spinal muscular atrophy (SMA), the most prevalent hereditary lower motor neuron disease, is caused by mutations in the telomeric copy of the survival of motor neuron ( SMN1 ) gene. Unlike other cells, lower motor neurons cannot tolerate low levels of smn protein. However, it is unclear as to the nature of the cell death involved. There is evidence that lower motor neurons undergo apoptosis in SMA, lead- ing to muscle weakness and wasting. This study investigated whether SMN1 regulation in a motor neuron model affected indices of apoptotic cell death. Decreased smn expression in neuroblas- toma hybrid (NSC-34) cell lines by small inter- fering RNA (siRNA) was demonstrated at the mRNA and protein level. Smn-depleted cells showed elevated caspase-3 activity, decreased cell viability and increased percentage of TUNEL positive cells. Conversely, NSC-34 cell smn over- expression by adenoviral gene transfer decreased staurosporine-induced caspase-3 elevation and mitigated induced cell toxicity as assessed by 3-(4,5-dimethyl thiazol-2-yl)-2,5-diphenyl tetra- zolium bromide (MTT) assay. However, increased smn expression by itself did not increase cell viability. These data suggest not only that decreased smn levels increase apoptosis in an in vitro model of SMA, but also that increased smn can protect against neural injury. Keywords: Apoptosis; Caspase-3; Adenoviral Vector; RNA Interference; siRNA INTRODUCTION Progressive spinal muscular atrophy (SMA) is the most prevalent hereditary motor neuron disease, characterized by selective degeneration and loss of the anterior horn cells of the spinal cord and brain- stem, leading to progressive weakness and atrophy of skeletal muscles (Murayama et al. , 1991; Talbot and Davies, 2001). Three clinical diagnoses have been described depending on the age of onset, clinical severity, achievement of motor skills, and age at death (Aran, 1850; Zerres and Rudnik- Schoneborn, 1995; also see review, Iannaccone and Burghes 2002). The condition is caused by homozygous muta- tions or deletions in the telomeric copy of the sur- vival motor neuron ( SMN ) gene at chromosome 5q13 (Brzustowicz et al. , 1990; Lefebvre et al. , 1995). The 38 kDa smn protein is found in the ribo- nucleoprotein complexes of all cells, as well as in the axonal growth cones of neurons (Fischer et al. , 1997; Francis et al. , 1998; Fan and Simard, 2002; Rossoll et al. , 2003). In the human, SMN is encod- ed by two genes, SMN1 and SMN2 , which differ by one nucleotide in exon 7, causing an exclusion of F.P. Graham Publishing Co. Survival Motor Neuron Protein Regulates Apoptosis in an in vitro Model of Spinal Muscular Atrophy GRAHAM C. PARKER a,b , XINGLI LI a , ROUMEN A. ANGUELOV a , GABOR TOTH a,# , ADAM CRISTESCU a and GYULA ACSADI a,c,* a Carman and Ann Adams Department of Pediatrics, Wayne State University, Detroit, MI; b Children's Research Center of Michigan, Wayne State University, Detroit, MI; c Department of Neurology, Wayne State University, Detroit, MI, USA. [email protected] # Current affiliation: University of Chicago, Department of Neurology
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