Cohen Rachael L, Margolis Russell L
aDepartment of Psychiatry and Behavioral Sciences, Division of Neurobiology, Johns Hopkins University School of Medicine bDepartment of Neurology cProgram of Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Curr Opin Neurol. 2016 Dec;29(6):735-742. doi: 10.1097/WCO.0000000000000385.
Spinocerebellar ataxia type 12 (SCA12) is a rare autosomal dominant neurodegenerative disease characterized by tremor, gait abnormalities, and neuropsychiatric syndromes. The location of the causative CAG/CTG expansion mutation in PPP2R2B, a gene encoding regulatory units of the protein phosphatase 2A, may provide unique insights into the pathogenesis of neurodegeneration.
The first neuropathological examination of a brain from an SCA12 patient revealed both cerebellar and cerebral cortical atrophy, with a noted loss of Purkinje cells and no evidence of polyglutamine aggregates. Molecular investigations have demonstrated considerable complexity of PPP2R2B, which appears to encode at least eight isoforms each with a different N-terminal region. The repeat potentially influences PPP2R2B expression, and is itself included in several splice variants, falling within an open reading frame of at least one of these variants.
The current data suggest at least two nonmutually exclusive hypotheses of SCA12 neurodegeneration. First, the repeat may influence PPP2R2B expression, by altering promoter activity, splicing, or transcript stability. This hypothesis would predict that the mutation changes the regulation of protein phosphatase 2A, with implications for the phosphoproteome. Alternatively, the repeat itself may be expressed and have toxic properties, though perhaps not through polyglutamine tracts. Either hypothesis may provide novel insight into the pathogenesis of neurodegeneration.
12型脊髓小脑共济失调（SCA12）是一种罕见的常染色体显性神经退行性疾病，其特征为震颤、步态异常和神经精神综合征。致病的CAG/CTG扩展突变位于PPP2R2B基因中，该基因编码蛋白磷酸酶2A的调节单位，这可能为神经退行性变的发病机制提供独特的见解。
对一名SCA12患者大脑进行的首次神经病理学检查显示，小脑和大脑皮质均有萎缩，浦肯野细胞明显丢失，且无多聚谷氨酰胺聚集物的证据。分子研究表明PPP2R2B相当复杂，它似乎编码至少八种亚型，每种亚型都有不同的N端区域。该重复序列可能影响PPP2R2B的表达，并且其本身包含在几种剪接变体中，位于这些变体中至少一种的开放阅读框内。
目前的数据提示了SCA12神经退行性变的至少两种并非相互排斥的假说。首先，该重复序列可能通过改变启动子活性、剪接或转录本稳定性来影响PPP2R2B的表达。这一假说预测该突变会改变蛋白磷酸酶2A的调节，对磷酸化蛋白质组有影响。另外，该重复序列本身可能会表达并具有毒性，尽管可能不是通过多聚谷氨酰胺序列。这两种假说都可能为神经退行性变的发病机制提供新的见解。
