CCP1 promotes mitochondrial fusion and motility to prevent Purkinje cell neuron loss in <i>pcd</i> mice

Abstract

A perplexing question in neurodegeneration is why different neurons degenerate. The Purkinje cell degeneration (<i>pcd</i>) mouse displays a dramatic phenotype of degeneration of cerebellar Purkinje cells. Loss of CCP1/Nna1 deglutamylation of tubulin accounts for <i>pcd</i> neurodegeneration, but the mechanism is unknown. In this study, we modulated the dosage of fission and fusion genes in a <i>Drosophila melanogaster</i> loss-of-function model and found that mitochondrial fragmentation and disease phenotypes were rescued by reduced Drp1. We observed mitochondrial fragmentation in CCP1 null cells and in neurons from <i>pcd</i> mice, and we documented reduced mitochondrial fusion in cells lacking CCP1. We examined the effect of tubulin hyperglutamylation on microtubule-mediated mitochondrial motility in <i>pcd</i> neurons and noted markedly reduced retrograde axonal transport. Mitochondrial stress promoted Parkin-dependent turnover of CCP1, and CCP1 and Parkin physically interacted. Our results indicate that CCP1 regulates mitochondrial motility through deglutamylation of tubulin and that loss of CCP1-mediated mitochondrial fusion accounts for the exquisite vulnerability of Purkinje neurons in <i>pcd</i> mice.