DLP1-dependent Mitochondrial Fragmentation And Redistribution Mediate Prion-associated Mitochondrial Dysfunction And Neuronal Death

Transmissible Spogiform Encephalopathies(TSEs),also known as Prion diseases,which are progressive fatal neurodegenerative diseases and pathologically characterized by brain vacuolation,neuronal cell death and astrocytosis.They are caused by the conversion of cellular prion protein(PrPC)into pathological isoform(PrPSc)through conformational changes.Mitochondrial malfunction is a universal and critical step in the pathogenesis of many neurodegenerative diseases including prion diseases.Dynamin-like protein 1(DLP1)is one of the key regulators of mitochondrial fission.Mitochondrial over-fission results in a mount loss of neurons,which is the symptom of neurodegenerative diseases such as Alzheimer disease(AD),Parkinson's disease(PD),Huntington's disease(HD),etc.In this study,we investigated the role of DLP1 in mitochondrial fragmentation and dysfunction in neurons using in vitro and in vivo prion disease models.Mitochondria became fragmented and redistributed from axons to soma,correlated with increased mitochondrial DLP1 expression in murine primary neurons(N2a cells)treated with the prion peptide PrP106-126 in vitro as well as in prion strain-infected hamster brain in vivo.Suppression of DLP1 expression by DPL1 RNAi inhibited prion-induced mitochondrial fragmentation and dysfunction(measured by ADP/ATP ratio,mitochondrial membrane potential and mitochondrial integrity).We also demonstrated that DLP1 RNAi is neuroprotective against prion peptide in N2a cells as shown by improved cell viability and decreased apoptosis markers,caspase 3 induced by PrP106-126.On the contrary,overexpression of DLP1 exacerbated mitochondrial dysfunction and cell death.Moreover,inhibition of DLPI expression ameliorated PrP106 126-induced neurite Ioss and synaptic abnormalities(i.e.loss of dendritic spine and PSD-95,a postsynaptic scaffolding protein as a marker of synaptic plasticity)in primary neurons,suggesting that altered DLP1 expression and mitochondrial fragmentation are upstream events that mediate PrP106-126-induced neuron loss and degeneration.Our findings suggest that DLP1-dependent mitochondrial fragmentation and redistribution plays a pivotal role in PrPSc-associated mitochondria dysfunction and neuron apoptosis.Inhibition of DLP1 may be a novel and effective strategy in the prevention and treatment of prion diseases.In this study,we demostated that DLP1-dependent mitochondrial fragmentation and redistribution mediate prion-associated mitochondrial dysfunction as well as neuronal death and degerneration.