Calcium signaling in Parkinson's disease

Cell Tissue Res. 2014 Aug;357(2):439-54. doi: 10.1007/s00441-014-1866-0. Epub 2014 May 1.

Abstract

Calcium (Ca(2+)) is an almost universal second messenger that regulates important activities of all eukaryotic cells. It is of critical importance to neurons, which have developed extensive and intricate pathways to couple the Ca(2+) signal to their biochemical machinery. In particular, Ca(2+) participates in the transmission of the depolarizing signal and contributes to synaptic activity. During aging and in neurodegenerative disease processes, the ability of neurons to maintain an adequate energy level can be compromised, thus impacting on Ca(2+) homeostasis. In Parkinson's disease (PD), many signs of neurodegeneration result from compromised mitochondrial function attributable to specific effects of toxins on the mitochondrial respiratory chain and/or to genetic mutations. Despite these effects being present in almost all cell types, a distinguishing feature of PD is the extreme selectivity of cell loss, which is restricted to the dopaminergic neurons in the ventral portion of the substantia nigra pars compacta. Many hypotheses have been proposed to explain such selectivity, but only recently it has been convincingly shown that the innate autonomous activity of these neurons, which is sustained by their specific Cav1.3 L-type channel pore-forming subunit, is responsible for the generation of basal metabolic stress that, under physiological conditions, is compensated by mitochondrial buffering. However, when mitochondria function becomes even partially compromised (because of aging, exposure to environmental factors or genetic mutations), the metabolic stress overwhelms the protective mechanisms, and the process of neurodegeneration is engaged. The characteristics of Ca(2+) handling in neurons of the substantia nigra pars compacta and the possible involvement of PD-related proteins in the control of Ca(2+) homeostasis will be discussed in this review.

Publication types

  • Review

MeSH terms

  • Animals
  • Brain / metabolism
  • Brain / pathology*
  • Calcium Signaling*
  • Dopaminergic Neurons / metabolism
  • Dopaminergic Neurons / pathology
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Mitochondria / metabolism
  • Mitochondria / pathology
  • Oncogene Proteins / metabolism
  • Parkinson Disease / metabolism*
  • Parkinson Disease / pathology*
  • Protein Deglycase DJ-1
  • Protein Kinases / metabolism
  • Protein Serine-Threonine Kinases / metabolism
  • Ubiquitin-Protein Ligases / metabolism
  • alpha-Synuclein / metabolism

Substances

  • Intracellular Signaling Peptides and Proteins
  • Oncogene Proteins
  • alpha-Synuclein
  • Ubiquitin-Protein Ligases
  • parkin protein
  • Protein Kinases
  • LRRK2 protein, human
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • PTEN-induced putative kinase
  • Protein Serine-Threonine Kinases
  • PARK7 protein, human
  • Protein Deglycase DJ-1