CCP1 promotes mitochondrial fusion and motility to prevent Purkinje cell neuron loss in pcd mice

&NA; A perplexing question in neurodegeneration is why different neurons degenerate. The Purkinje cell degeneration (pcd) mouse displays a dramatic phenotype of degeneration of cerebellar Purkinje cells. Loss of CCP1/Nna1 deglutamylation of tubulin accounts for pcd neurodegeneration, but the mechanism is unknown. In this study, we modulated the dosage of fission and fusion genes in a Drosophila melanogaster 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 pcd mice, and we documented reduced mitochondrial fusion in cells lacking CCP1. We examined the effect of tubulin hyperglutamylation on microtubule‐mediated mitochondrial motility in pcd 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 pcd mice. &NA; Purkinje cells rapidly degenerate in pcd mice due to loss of function of tubulin deglutamylase cytosolic carboxypeptidase 1 (CCP1), which promotes mitochondrial fusion in a Drosophila model, CCP1 null cells, and pcd neurons. The CCP1‐mediated increase in mitochondrial motility accounts for CCP1‐dependent mitochondrial fusion, underscoring the linkage between regulation of mitochondria dynamics, mitochondria motility, and Purkinje neuron survival.