Life on the edge: Determinants of selective neuronal vulnerability in Parkinson's disease

Dalton James Surmeier Jr*, Enrico Zampese, Daniel Galtieri, Paul T Schumacker

*Corresponding author for this work

Research output: Chapter in Book/Report/Conference proceedingChapter

Abstract

One of the defining features of Parkinson's disease (PD) is its sparsely distributed pathology. This chapter explores the hypothesis that this selective vulnerability can be traced back to an unusual neuronal phenotype. This phenotype is best exemplified by dopaminergic neurons in the substantia nigra pars compacta (SNc), whose loss is responsible for the cardinal motor symptoms of PD. These neurons have extraordinarily long and branched axons, sustained autonomous spiking, and elevated levels of cytosolic Ca 2+ , in addition to a chemically reactive neurotransmitter. This combination of features leads to sustained elevations in mitochondrial oxidative stress, possibly as a consequence of the reliance on feedforward control of mitochondrial metabolism, and to increased susceptibility to alpha-synuclein (aSYN) aggregation. These derivative features could increase the impact of aging, genetic mutations, and environmental toxins linked to increased risk of PD, providing a unifying theory of PD pathogenesis. Although most of these traits are not amenable to therapeutic manipulation, Ca2+ loading is indeed, because it stems from opening of Cav1 (L-type) Ca 2+ channels-channels that are antagonized by dihydropyridine drugs long used for the treatment of hypertension. Epidemiological studies have revealed that the use of dihydropyridines is associated with a reduced risk of developing PD. As a consequence, a large phase III clinical trial is underway in North America to determine if one of the dihydropyridines (isradipine) can slow PD progression.

Original languageEnglish (US)
Title of host publicationMitochondrial Dysfunction in Neurodegenerative Disorders
Subtitle of host publicationSecond Edition
PublisherSpringer International Publishing
Pages141-173
Number of pages33
ISBN (Electronic)9783319286372
ISBN (Print)9783319286358
DOIs
StatePublished - Jun 8 2016

Keywords

  • Bioenergetics
  • Calcium
  • Dopamine
  • Electrophysiology
  • Mitochondria redox
  • Pacemaking oxidative stress
  • Parkinson's disease
  • Selective vulnerability
  • Substantia nigra
  • Two-photon microscopy

ASJC Scopus subject areas

  • Neuroscience(all)

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