Humanin attenuates apoptosis induced by DRPLA proteins with expanded polyglutamine stretches
Humanin attenuates apoptosis induced by DRPLA proteins with expanded polyglutamine stretches
复制标题
DOI：
10.1385/jmn:25:2:165
复制
发表时间：
2005-01-01
影响因子：
3.1
通讯作者：
Uenol, S
中科院分区：
文献类型：
--
作者：
Kariya, S;Hirano, M;Uenol, S
Dentatorubral-pallidoluysianatrophy（DRPLA）是一种常染色体显性遗传的神经退行性疾病，由DRPLA基因中CAG重复序列扩增引起，该基因编码多聚谷氨酰胺（polyQ）延伸。已知扩增的polyQ形成细胞内聚集体并赋予神经毒性活性。最近的研究表明，凋亡信号调节激酶1（ASK 1）的激活参与了polyQ诱导的细胞凋亡。Humanin（HN）是一种内源性肽，其抑制由突变的阿尔茨海默病基因引起的神经元细胞死亡，并且这种神经保护因子最近被报道通过抑制ASK 1的激活来抑制细胞凋亡。为了测试HN对polyQ神经毒性的抗ASK 1作用，我们在Tet-Off（TM）系统的控制下构建了表达扩增的polyQ的神经元PC 12细胞。使用该细胞系，我们表明HN抑制由扩增的polyQs诱导的凋亡性细胞死亡。然而，这种抑制是不完全的，这表明polyQs还刺激了与ASK 1无关的其他致病级联反应。我们进一步表明HN抑制polyQ聚集体形成。该结果暗示了聚集也与涉及ASK 1活化的polyQ介导的级联反应相关的可能性。虽然细节仍不确定，但我们的研究结果表明，ASK 1可能参与DRPLA的发病机制，HN可能部分抑制polyQ疾病中的神经变性。
Dentatorubral-pallidoluysianatrophy (DRPLA) is an autosomal-dominantneurodegenerative disorder caused by expansion of CAG repeats in the DRPLA gene, which codes for a polyglutamine (polyQ) stretch. The expanded polyQs are known to form intracellular aggregates and to confer neurotoxic activity. Recent studies have indicated that activation of apoptosis signal-regulating kinase 1 (ASK1) is involved in polyQ-induced apoptosis. Humanin (HN) is an endogenous peptide that inhibits neuronal cell death caused by mutant Alzheimer's disease genes, and this neuroprotective factor has recently been reported to suppress apoptosis by inhibiting activation of ASK1. To test the anti-ASK1 effect of HN on polyQ neurotoxicity, we constructed neuronal PC12 cells expressing expanded polyQs under the control of the Tet-Off (TM) system. Using this cell line, we showed that HN suppresses apoptotic cell death induced by expanded polyQs. However, the suppression was incomplete, suggesting that polyQs also stimulate other pathogenic cascades unrelated to ASK1. We further showed that HN suppresses polyQ aggregate formation. This result implied the possibility that aggregation is also related to the polyQ-mediated cascade involving ASK1 activation. Although the details remain uncertain, our results suggest that ASK1 is potentially involved in pathogenesis of DRPLA and that HN might contribute partially to the suppression of neurodegeneration in polyQ diseases.