Disruption of SUMO-Specific Protease 2 Induces Mitochondria Mediated Neurodegeneration

Post-translational modification of proteins by small ubiquitin-related modifier (sumo) is reversible and highly evolutionarily conserved from yeasts to humans. unlike ubiquitination with a well-established role in protein degradation,sumoylation may alter protein function,activity,stability and subcellular localization. members of sumo-specific protease (senp) family,capable of sumo removal,are involved in the reversed conjugation process. although sumo-specific proteases are known to reverse sumoylation in many well-defined systems,their importance in mammalian development and pathogenesis remains largely elusive. in patients with neurodegenerative diseases,aberrant accumulation of sumo-conjugated proteins has been widely described. several aggregation-prone proteins modulated by sumo have been implicated in neurodegeneration,but there is no evidence supporting a direct involvement of sumo modification enzymes in human diseases. here we show that mice with neural-specific disruption of senp2 develop movement difficulties which ultimately results in paralysis. the disruption induces neurodegeneration where mitochondrial dynamics is dysregulated. senp2 regulates drp1 sumoylation and stability critical for mitochondrial morphogenesis in an isoform-specific manner. although dispensable for development of neural cell types,this regulatory mechanism is necessary for their survival. our findings provide a causal link of sumo modification enzymes to apoptosis of neural cells,suggesting a new pathogenic mechanism for neurodegeneration. exploring the protective effect of senp2 on neuronal cell death may uncover important preventive and therapeutic strategies for neurodegenerative diseases. © 2014 fu et al.