'Rejuvenation' protects neurons in mouse models of Parkinson's disease

Nature. 2007 Jun 28;447(7148):1081-6. doi: 10.1038/nature05865. Epub 2007 Jun 10.

Abstract

Why dopamine-containing neurons of the brain's substantia nigra pars compacta die in Parkinson's disease has been an enduring mystery. Our studies suggest that the unusual reliance of these neurons on L-type Ca(v)1.3 Ca2+ channels to drive their maintained, rhythmic pacemaking renders them vulnerable to stressors thought to contribute to disease progression. The reliance on these channels increases with age, as juvenile dopamine-containing neurons in the substantia nigra pars compacta use pacemaking mechanisms common to neurons not affected in Parkinson's disease. These mechanisms remain latent in adulthood, and blocking Ca(v)1.3 Ca2+ channels in adult neurons induces a reversion to the juvenile form of pacemaking. Such blocking ('rejuvenation') protects these neurons in both in vitro and in vivo models of Parkinson's disease, pointing to a new strategy that could slow or stop the progression of the disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / pharmacology
  • Aging
  • Animals
  • Antiparkinson Agents / pharmacology
  • Calcium / metabolism
  • Calcium / pharmacology
  • Calcium Channels, L-Type / deficiency
  • Calcium Channels, L-Type / genetics
  • Calcium Channels, L-Type / metabolism*
  • Dendrites / metabolism
  • Disease Models, Animal*
  • Disease Progression
  • Dopamine / metabolism
  • Electric Conductivity
  • Gene Deletion
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mitochondria / drug effects
  • Models, Neurological*
  • Neurons / cytology*
  • Neurons / drug effects
  • Neurons / metabolism
  • Neurons / pathology*
  • Parkinson Disease / drug therapy
  • Parkinson Disease / metabolism
  • Parkinson Disease / pathology*
  • Parkinson Disease / prevention & control
  • Rotenone / pharmacology
  • Substantia Nigra / cytology
  • Substantia Nigra / metabolism
  • Substantia Nigra / pathology

Substances

  • Antiparkinson Agents
  • Cacna1d protein, mouse
  • Calcium Channels, L-Type
  • Rotenone
  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
  • Calcium
  • Dopamine