title: Calcium and Parkinson's disease.
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.
authors: Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, 60611, Illinois, USA. Electronic address: j-surmeier@northwestern.edu.
authors: D James
authors: DJ
authors: Surmeier
authors: Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, 60611, Illinois, USA.
authors: Paul T
authors: PT
authors: Schumacker
authors: Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, 60611, Illinois, USA.
authors: Jaime D
authors: JD
authors: Guzman
authors: Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, 60611, Illinois, USA.
authors: Ema
authors: E
authors: Ilijic
authors: Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, 60611, Illinois, USA.
authors: Ben
authors: B
authors: Yang
authors: Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, 60611, Illinois, USA.
authors: Enrico
authors: E
authors: Zampese
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D006801:Humans; D017136:Ion Transport; D009474:Neurons / Q000378:metabolism; D010300:Parkinson Disease / Q000378:metabolism* / Q000473:pathology
chemical_list: D020746:Calcium Channels, L-Type; D002118:Calcium
keywords: Dopamine; Electrophysiology; Endoplasmic reticulum; Mitochondria; Oxidant stress; Substantia nigra; Two photon microscopy