Co-regulation of survival of motor neuron and Bcl-xL expression: implications for neuroprotection in spinal muscular atrophy.

Spinal muscular atrophy (SMA), a fatal genetic motor disorder of infants, is caused by diminished full-length survival of motor neuron (SMN) protein levels. Normally involved in small nuclear ribonucleoprotein (snRNP) assembly and pre-mRNA splicing, recent studies suggest that SMN plays a critical role in regulating apoptosis. Interestingly, the anti-apoptotic Bcl-x isoform, Bcl-xL, is reduced in SMA. In a related finding, Sam68, an RNA-binding protein, was found to modulate splicing of SMN and Bcl-xL transcripts, promoting SMNΔ7 and pro-apoptotic Bcl-xS transcripts. Here we demonstrate that Bcl-xL expression increases SMN protein by ∼2-fold in SH-SY5Y cells. Conversely, SMN expression increases Bcl-xL protein levels by ∼6-fold in SH-SY5Y cells, and ∼2.5-fold in the brains of transgenic mice over-expressing SMN (PrP-SMN). Moreover, Sam68 protein levels were markedly reduced following SMN and Bcl-xL expression in SH-SY5Y cells, suggesting a feedback mechanism co-regulating levels of both proteins. We also found that exogenous SMN expression increased full-length SMN transcripts, possibly by promoting exon 7 inclusion. Finally, co-expression of SMN and Bcl-xL produced an additive anti-apoptotic effect following PI3-kinase inhibition in SH-SY5Y cells. Our findings implicate Bcl-xL as another potential target in SMA therapeutics, and indicate that therapeutic increases in SMN may arise from modest increases in total SMN.

Experience of ApoE study in Thai elderly.

UNLABELLED: The association between ApoE E4 and dementia is reported in Alzheimer's disease and other dementia such as in multi-infarct dementia. OBJECTIVES: To examine the association between apolipoprotein E genotype (ApoE) and dementia in Thai elderly and patients to examine the alleles frequencies of ApoE in a Thai population. MATERIAL AND METHOD: Seventy-eight cases and ninety-four controls from a community based population were recruited. Their ages were all over 50 years. Dementia was diagnosed by DSM IV criteria. Blood was taken and stored for DNA extraction and for restriction enzyme analysis of ApoE genotype. Descriptive analysis and odds ratios from SPSS 9.0 program were used in this study. RESULTS: Alleles frequencies of ApoE E2, E, E4 in normal controls were 0.03, 0.80, 0.17 and alleles frequencies of ApoE E3, E4 in dementia subjects were 0.71 and 0.29, respectively. Odds ratios for dementia risk of apolipoprotein genes were as follows: 0.62 for ApoE E3 and 1.98 for ApoE E4. In this study, forty-two dementia subjects had Alzheimer's disease. Fifty nine point five per cent of Alzheimer's disease subjects carried ApoE E4 (positive predictive value is 0.60). CONCLUSION: Thai elderly carry ApoE genotype distribution similar to that reported in other ethnic groups. Bearing ApoE E4 gene increases the risk of developing dementia. The use of ApoE genotyping can only be a diagnostic adjunct for Alzheimer's disease.