Autophagy precedes apoptosis among at risk cerebellar Purkinje cells in the shaker mutant rat: an ultrastructural study.

Cerebellar Purkinje cell (PC) death has been shown to occur in essential tremor, ataxia, and many other neurodegenerative diseases in humans. Shaker mutant rats have an X-linked recessive mutation that causes hereditary degeneration of "at risk" cerebellar PCs. This defect can occur in the restricted anterior (ADC) and posterior (PDC) vermal degeneration compartments postnatally within 7 to 14 weeks of age as a natural phenotype in the shaker mutant rat. "Secure" PCs persist in a flocculonodular survival compartment (FNSC). Because we have previously shown that "at risk" PCs die due to apoptosis in the shaker mutant rat, we hypothesized that the PC death observed in the hereditary shaker mutant rat may be due to the activation of more than one type of death pathway. This ultrastructural investigation suggests that "at risk" PCs die due to apoptosis as a result of autophagic activation. Moreover, our data suggest that both apoptosis and autophagy must be simultaneously inhibited to rescue "at risk" PCs from death.