Alpha-synuclein-induced neurodegeneration is exacerbated in PINK1 knockout mice

Neurobiol Aging. 2014 Nov;35(11):2625-2636. doi: 10.1016/j.neurobiolaging.2014.04.032. Epub 2014 Jun 14.

Abstract

Loss-of-function mutations in the PINK1 gene lead to recessive forms of Parkinson's disease. Animal models with depleted PINK1 expression have failed to reproduce significant nigral dopaminergic neurodegeneration and clear alpha-synuclein pathology, main characteristics of the disease. In this study, we investigated whether alpha-synuclein pathology is altered in the absence of PINK1 in cell culture and in vivo. We observed that downregulation of PINK1 enhanced alpha-synuclein aggregation and apoptosis in a neuronal cell culture model for synucleinopathy. Silencing of PINK1 expression in mouse substantia nigra using recombinant adeno-associated viral vectors did not induce dopaminergic neurodegeneration in a long-term study up to 10 months, nor did it enhance or accelerate dopaminergic neurodegeneration after alpha-synuclein overexpression. However, in PINK1 knockout mice, overexpression of alpha-synuclein in the substantia nigra resulted in enhanced dopaminergic neurodegeneration as well as significantly higher levels of alpha-synuclein phosphorylation at serine 129 at 4 weeks postinjection. In conclusion, our results demonstrate that total loss of PINK1 leads to an increased sensitivity to alpha-synuclein-induced neuropathology and cell death in vivo.

Keywords: AAV; Aggregation; Knockdown; Knockout; Mouse; Neurodegeneration; PINK1; Parkinson's disease; Phosphorylation; α-Synuclein.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Cells, Cultured
  • Disease Progression
  • Down-Regulation
  • Gene Expression
  • Humans
  • Mice, Knockout
  • Mutation
  • Neurodegenerative Diseases / genetics*
  • Neurodegenerative Diseases / pathology
  • Neurons / pathology
  • Parkinson Disease / genetics*
  • Parkinson Disease / pathology
  • Phosphorylation
  • Protein Aggregates
  • Protein Aggregation, Pathological / genetics*
  • Protein Aggregation, Pathological / pathology
  • Protein Kinases / deficiency
  • Protein Kinases / genetics*
  • Substantia Nigra / metabolism
  • alpha-Synuclein / metabolism*

Substances

  • Protein Aggregates
  • alpha-Synuclein
  • Protein Kinases
  • PTEN-induced putative kinase