INVESTIGATION OF THE SYNERGIC EFFECT OF β-SYNUCLEIN WITH HSP27 ON NEUROPROTECTION

两个错义突变近年来，在Lewy Bosses痴呆中发现了α-突触核蛋白的同源物β-突触核蛋白的突变（P123 H和V70 M），但这些突变影响Lewy Bosses痴呆发病的机制尚不清楚，为了阐明β-突触核蛋白突变在神经退行性变中的作用，每种突变体都能稳定地转染入B103神经母细胞瘤细胞中。过表达突变的β-突触核蛋白的细胞具有增强的溶酶体活性和胞浆中溶酶体包涵体的能力，提示β_突触核蛋白的错义突变可能是诱发神经元变性的原因之一。随后，我们用THY-1启动子建立了过表达P123 β-突触核蛋白的转基因小鼠。小鼠出现轴突变性和突触肿胀，与蛋白质聚集和行为异常（包括运动功能障碍）相关。因此，这些转基因小鼠可用作新的突触核变性模型小鼠。进一步的研究正在进行中，包括在P123 H β-突触核蛋白转基因小鼠和α-突触核蛋白转基因小鼠之间建立双基因小鼠。

TWO MISSENSE MUTATIONS (P123H AND V70M) OF BETA-SYNUCLEIN, THE HOMOLOGUE OF ALPHA-SYNUCLEIN, HAVE BEEN RECENTLY IDENTIFIED IN DEMENTIA WITH LEWY BODIES, HOWEVER, THE MECHANISM THROUGH WHICH THESE MUTATIONS INFLUENCE THE PATHOGENESIS OF DEMENTIA WITH LEWY BODIES IS UNCLEAR, TO INVESTIGATE THE ROLE OF THE BETA-SYNUCLEIN MUTATIONS IN NEURODEGENERATION, EACH MUTANT WAS STABLY TRANSFECTED INTO B103 NEUROBLASTOMA CELLS CELLS OVEREXPRESSING MUTATED BETA-SYNUCLEIN HAD ENHANCED LYSOSOMAL, ACTIVITY AND LYSOSOMAL INCLUSION BODIES IN THE CYTOPLASM, SUGGESTING THAT THESE MISSENSE MUTATIONS OF BETA_SYNUCLEIN MIGHT PLAY A CAUSATIVE ROLE IN STIMULATING NEURODEGENETION. SUBSEQUENTLY, WE CREATED TRANSGENIC MICE OVEREXPRESSING P123H BETA-SYNUCLEIN USING THY-1 PROMOTER. THE MICE EXHIBITED AXONAL DEGENERATION AND SYNAPTIC TERMINAL SWELLING, ASSOCIATED WITH PROTEIN AGGREGATION AND BEHAVIOURAL ABNORMALITIES, INCLUDING MOTER DYSFUNCTION. THUS, THESE TRANSGENIC MICE MAY BE USEFUL AS NEW SYNUCLEINOPATHY MODEL MICE. FURTHER STUDY IS IN PROGRESS, INCLUDING CREATION OF BIGENIC MICE BETWEEN P123H BETA-SYNUCLEIN TRANSGENIC MICE AND ALPHA-SYNUCLEIN TRANSGENIC MICE.