Calcium and Parkinson's disease

Dalton James Surmeier Jr*, Paul T Schumacker, Jaime D. Guzman, Ema Ilijic, Ben Yang, Enrico Zampese

*Corresponding author for this work

Research output: Contribution to journalReview article

59 Scopus citations

Abstract

Parkinson's disease (PD) is the second most common neurodegenerative disease in the world. Its causes are poorly understood and there is no proven therapeutic strategy for slowing disease progression. The core motor symptoms of PD are caused by the death of dopaminergic neurons in the substantia nigra pars compacta (SNc). In these neurons, Ca2+entry through plasma membrane Cav1 channels drives a sustained feed-forward stimulation of mitochondrial oxidative phosphorylation. Although this design helps prevent bioenergetic failure when activity needs to be sustained, it leads to basal mitochondrial oxidant stress. Over decades, this basal oxidant stress could compromise mitochondrial function and increase mitophagy, resulting in increased vulnerability to other proteostatic stressors, like elevated alpha synuclein expression. Because this feedforward mechanism is no longer demanded by our lifestyle, it could be dispensed with. Indeed, use of dihydropyridines – negative allosteric modulators of Cav1 Ca2+ channels – comes with little or no effect on brain function but is associated with decreased risk and progression of PD. An ongoing, NIH sponsored, Phase 3 clinical trial in North America is testing the ability of one member of the dihydropyridine class (isradipine) to slow PD progression in early stage patients. The review summarizes the rationale for the trial and outlines some unanswered questions.

Original languageEnglish (US)
Pages (from-to)1013-1019
Number of pages7
JournalBiochemical and Biophysical Research Communications
Volume483
Issue number4
DOIs
Publication statusPublished - Feb 19 2017

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Keywords

  • Dopamine
  • Electrophysiology
  • Endoplasmic reticulum
  • Mitochondria
  • Oxidant stress
  • Substantia nigra
  • Two photon microscopy

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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