Motoneuron specific calcium dysregulation and perturbed cellular calcium homestasis in amyotrophic lateral sclerosis: Recent advances gained from genetically modified animals and cell culture models

Manoj Kumar Jaiswal

Research output: Chapter in Book/Report/Conference proceedingChapterpeer-review

4 Scopus citations

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the selective loss of defined subgroups of motoneuorn populations in the brainstem and spinal cord with signature hallmarks of mitochondrial Ca2+ overload, free radical damage, excitotoxicity and impaired axonal transport. Although intracellular disruptions of cytosolic and mitochondrial calcium and in particular low cytosolic calcium ([Ca2+]i) buffering and a strong interaction between metabolic mechanisms and [Ca2+]i have been associated with selective motoneuron degeneration, the underlying mechanisms are not well understood. The present evidence supports a hypothesis that mitochondria are a primary target of mutant superoxide dismutase1 (mtSOD1)-mediated toxicity in ALS and intracellular alterations of cytosolic and mitochondria-ER microdomain calcium accumulation might aggravate the course of this neurodegenerative disease. Furthermore, chronic excitotoxicity mediated by Ca2+- permeable AMPA and NMDA receptors seems to initiate a vicious cycle of intracellular calcium dysregulation which leads to toxic Ca2+ overload and thereby selective neurodegeneration. Recent advancement in the experimental analysis of calcium signals at high spatiotemporal precision has allowed investigations of calcium regulation in different cell types, in particular selectively vulnerable/resistant cell types in different animal models of this motoneuron disease. This chapter provides an overview of recent advances in this field and discusses in detail what has been learned about Ca2+ homeostasis and the role of mitochondria in motoneurons in pathophysiological conditions such as ALS.

Original languageEnglish
Title of host publicationMotor Neuron Diseases
Subtitle of host publicationCauses, Classification and Treatments
PublisherNova Science Publishers, Inc.
Pages75-102
Number of pages28
ISBN (Print)9781614701019
StatePublished - Feb 2012
Externally publishedYes

Keywords

  • Amyotrophic lateral sclerosis
  • Calcium buffer
  • Calcium dysregulation
  • Mitochondria
  • Motoneuron
  • Selective vulnerability

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