A molecular basis for the increased vulnerability of substantia nigra dopamine neurons in aging and Parkinson's disease

C. Savio Chan, Tracy S. Gertler, D. James Surmeier*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

76 Scopus citations

Abstract

Parkinson's disease (PD) is a common neurodegenerative disorder of unknown etiology. There is no cure or proven strategy for slowing the progression of the disease. Although there are signs of pathology in many brain regions, the core symptoms of PD are attributable to the selective degeneration of dopaminergic neurons in the substantia nigra pars compacta. A potential clue to the vulnerability of these neurons is an increasing reliance with age upon L-type Ca2+ channels with a pore-forming Cav1.3 subunit to support autonomous activity. This reliance could pose a sustained stress on mitochondrial ATP generating oxidative phosphorylation, accelerating cellular aging and death. Systemic administration of isradipine, a dihydropyridine blocker of these channels, forces dopaminergic neurons in rodents to revert to a juvenile, L-type Ca2+ channel independent mechanism to generate autonomous activity. This "rejuvenation" confers protection against toxins that produce experimental Parkinsonism, pointing to a potential neuroprotective strategy for PD. Their decades-long track record of safe use in the treatment of hypertension makes dihydropyridines particularly attractive as a therapeutic tool in PD.

Original languageEnglish (US)
Pages (from-to)S63-S70
JournalMovement Disorders
Volume25
Issue numberSUPPL. 1
DOIs
StatePublished - 2010

Keywords

  • Aging
  • Dopamine
  • Neurons
  • Parkinson's disease
  • Substantia nigra

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

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