Inappropriate Intrusion of an Axonal Mitochondrial Anchor into Dendrites Causes Neurodegeneration

Syntaphilin (SNPH) is a major mitochondrial anchoring protein targeted to axons and excluded from dendrites. In this study, we provide in vivo evidence that this spatial specificity is lost in Shiverer (Shi) mice, a model for progressive multiple sclerosis (MS), resulting in inappropriate intrusion of SNPH into dendrites of cerebellar Purkinje cells with neurodegenerative consequences. Thus, reconstituting dendritic SNPH intrusion in SNPH-KO mice by viral transduction greatly sensitizes Purkinje cells to excitotoxicity when the glutamatergic climbing fibers are stimulated. Finally, we demonstrate in vitro that overexpression of SNPH in dendrites compromises neuronal viability by inducing N-methyl-D-aspartate (NMDA) excitotoxicity, reducing mitochondrial calcium uptake, and interfering with quality control of mitochondria by blocking somal mitophagy. Collectively, we propose that inappropriate immobilization of dendritic mitochondria by SNPH intrusion produces excitotoxicity and suggest that interception of dendritic SNPH intrusion is a therapeutic strategy to combat neurodegeneration. [Display omitted] •Axonal mitochondrial anchor SNPH intrudes into dendrites of progressive MS model•Dendritic SNPH sensitizes neurons to excitotoxicity and reduces [Ca2+]mito uptake•Dendritic SNPH degrades mitochondrial quality by impeding somal mitophagy•Intercepting dendritic SNPH intrusion could be a therapeutic target in MS Joshi et al. show that an axon-specific mitochondrial anchoring protein, Syntaphilin, invades dendrites in the progressive multiple sclerosis (MS) mouse model Shiverer. Dendritic SNPH intrusion sensitizes neurons to excitotoxicity, alters mitochondrial Ca2+ buffering, and impedes somal mitophagy, suggesting interception of dendritic SNPH intrusion as a therapeutic strategy in MS.