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DLP1-dependent mitochondrial fragmentation and redistribution mediate prion-associated mitochondrial dysfunction and neuronal death.

Abstract：

: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. 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 DLP1 expression ameliorated PrP106-126 -induced neurite loss 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.

journal_name

Aging Cell

journal_title

Aging cell

authors

Li C,Wang D,Wu W,Yang W,Ali Shah SZ,Zhao Y,Duan Y,Wang L,Zhou X,Zhao D,Yang L

doi

10.1111/acel.12693

subject

Has Abstract

pub_date

2018-02-01 00:00:00

issue

eissn

1474-9718

issn

1474-9726

journal_volume

pub_type

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DLP1-dependent mitochondrial fragmentation and redistribution mediate prion-associated mitochondrial dysfunction and neuronal death.