Submitted 10 september 2007 revised 23 november 2007

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(Submitted 10 September 2007; Revised 23 November 2007; In final form 23 November 2007) *Corresponding author: Tel.: 1 313-577-5906; FAX: 1 313-745-0955; E-mail: [email protected] ISSN 1029 8428 print/ ISSN 1476-3524 online. © 2008 FP Graham Publishing Co., Neurotoxicity Research, 2008, VOL. 13(1). pp. 39-48
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G.C. PARKER et al. 40 this exon from the majority of transcripts (SMN 7) (Lefebvre et al. , 1995). A loss of SMN may affect spliceosomal (snRNP) biogenesis and pre-mRNA splicing (reviewed by Eggert et al. , 2006). However, it is not yet known how SMN contributes to the functional integrity of cells (see, for review, Gubitz et al. , 2004). SMN is found in the cytoplasm, nucleolus and also nuclear 'gems' (gemini of coiled bodies) (Young et al. , 2000; 2001). Even though the genetic basis of SMA is well understood, it is not clear how defects in these ubiquitous processes result in motor neuron degen- eration, leaving other tissues unaffected. A com- plete loss of smn in mouse is lethal at an early embryonic stage (Schrank et al. , 1997). In trans- genic SMA mice a 20 to 35 percent of "wild-type" smn levels can rescue the embryonic lethality but unlike most cells in the body, lower motor neurons cannot tolerate the low level of smn (Hsieh-Li et al. , 2000; Monani et al. , 2000a,b). SMN 7 mice, SMN2+/+; SMN 7+/+; Smn-/- (Le et al. , 2005), are born with the same number of ostensibly nor- mal motor neurons as wild type mice. However, by day five there is observable motor neuron impairment, with motor neuron death occurring at postnatal day nine (Le et al. , 2005). However, as recently discussed by Nielsen et al. (2007), how the various regulatory elements contribute to the exon skipping responsible for the variably low- ered levels of smn production are yet to be eluci- dated (Nielsen et al. , 2007). Motor neuron death is a normal part of develop- ment. Histological observation of SMA notes the protracted nature of the cell death with irregular nuclear features being observable at gestational week sixteen and beyond, long after the last observed motor neuron death in normal tissue at gestational week twelve (Hayashi et al. , 1998; Fidzianska and Rafalowska, 2002; Soler-Botija et al. , 2002). Selective degeneration with nuclear chromatolysis of anterior horn cells has been described in SMA animal models (Hsieh-Li et al. , 2000; Jablonka et al. , 2000; Ferri et al. , 2004). Blastocyte cells in SMN null mouse embryos die from massive apoptosis (Schrank et al. , 1997). SMN1 itself has been associated with proteins known to participate in apoptosis, in particular with p53 (Vyas et al. , 2002; Young et al. , 2002), and ZFP1 (Gangwani et al. , 2005; Doran et al. , 2006; Gangwani, 2006). There is existing evi- dence that smn can be neuroprotective against apoptosis, with the mutant forms of SMN derived from SMA patients actually increas- ing viral-induced apoptosis (Kerr et al. , 2000). It was also shown that fibroblast from SMA patients were susceptible to camptothecin- induced apoptosis but protected by SMN gene transfer (Wang et al. , 2005).
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