感覚神経細胞とPurkinje細胞に共通する神経変性の原因はあるのか―常染色体劣性遺伝性脊髄小脳変性症の解明から学ぶこと

Clue for common mechanism of neuronal degeneration: a lesson from the autosomal recessive inherited ataxias

　劣性遺伝性脊髄小脳変性症は，後根神経節の感覚神経細胞，もしくは小脳のPurkinje細胞に変性の主体がある疾患群である。判明した原因遺伝子は多岐に及ぶが，代表的なものの分類を試みると，1）膜における酸化ストレス調節の障害に関するもの，2）酸化ストレスに対するミトコンドリアの機能異常に関するもの，3）核DNAの修復障害に関するものに分類される。感覚神経細胞の障害は数年にわたり進行性であり，蓄積された障害により神経変性が引き起こされると推察される。一方，Purkinje細胞の変性の程度は強弱があり，核DNAの修復障害に問題がある例に強い。核DNAの修復障害では一本鎖DNA修復，とくに塩基除去修復との関連が注目されている。塩基除去修復は神経細胞内でのDNA修復の主体であり，またミトコンドリアのDNA修復も司っている。塩基除去修復は主として酸化ストレスや脱プリン，脱アミノによる内因性のDNA障害を修復する。酸化ストレスとDNA修復は，これらの疾患に共通する変性機構の解明の手がかりとなる可能性がある。

　Autosomal recessive inherited spinocerebellar ataxias（ARSCD）are diseases which affect sensory neuron in dorsal root ganglia and Purkinje neuron in cerebellum. Recently several causative genes for ARSCDs have been identified. The functional analysis of causative genes of ARSCDs allows us to consider the common mechanism of neurodegeneration in specific neuronal cells. We may categorize the pathogenesis of ARSCDs into three groups 1）dysregulation of oxidative stress in membrane, 2）mitochondria dysfunction due to oxidative stress, 3）impairment of DNA repair. The sensory nerve neurons in dorsal root ganglia degenerate in all of these diseases. It takes for several years to develop degeneration in sensory nerve neurons. We speculate the accumulation of some kind of damages in the neurons by time cause neuronal cell degeneration. However the degree of degeneration of Purkinje cell is different among the disease. The diseases caused by impairment of nuclear DNA system affect Purkinje neuron more severely than the diseases, which caused by dysregulation of oxidative stress or mitochondrial dysfunction due to oxidative stress. In human cells there are several pathway to repair DNA. Recently the impairment of base excision repair system（BER）is notable for neuronal degeneration. The BER is also known as the only system which repair mitochondrial DNA. The BER system mainly repairs the DNA injury caused by oxidative stress. These findings suggested us the impairment of oxidative stress surveillance system is important for pathogenesis of neurodegeneration in ARSCDs. The study of the common neurodegenerative pathway among these disorders will open the new strategy to prevent the degenerative process in sensory neuron and Purkinje cells.