A viral peptide that targets mitochondria protects against neuronal degeneration in models of Parkinson's disease

Nat Commun. 2014 Oct 21;5:5181. doi: 10.1038/ncomms6181.

Abstract

Mitochondrial dysfunction is a common feature of many neurodegenerative disorders, notably Parkinson's disease. Consequently, agents that protect mitochondria have strong therapeutic potential. Here, we sought to divert the natural strategy used by Borna disease virus (BDV) to replicate in neurons without causing cell death. We show that the BDV X protein has strong axoprotective properties, thereby protecting neurons from degeneration both in tissue culture and in an animal model of Parkinson's disease, even when expressed alone outside of the viral context. We also show that intranasal administration of a cell-permeable peptide derived from the X protein is neuroprotective. We establish that both the X protein and the X-derived peptide act by buffering mitochondrial damage and inducing enhanced mitochondrial filamentation. Our results open the way to novel therapies for neurodegenerative diseases by targeting mitochondrial dynamics and thus preventing the earliest steps of neurodegenerative processes in axons.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Axons / metabolism
  • Axons / physiology
  • Disease Models, Animal
  • Female
  • HEK293 Cells
  • Humans
  • Male
  • Membrane Potential, Mitochondrial
  • Mice
  • Mice, Inbred C57BL
  • Microfluidics
  • Microscopy, Confocal
  • Microscopy, Fluorescence
  • Mitochondria / pathology*
  • Neurodegenerative Diseases / prevention & control*
  • Neurodegenerative Diseases / virology
  • Neurons / metabolism
  • Parkinson Disease / prevention & control*
  • Parkinson Disease / virology
  • Peptides / chemistry*
  • Phosphorylation
  • Rats
  • Rats, Sprague-Dawley
  • Reactive Oxygen Species / metabolism
  • Rotenone / chemistry
  • Viral Nonstructural Proteins / chemistry*

Substances

  • Peptides
  • Reactive Oxygen Species
  • Viral Nonstructural Proteins
  • Rotenone