Mitochondrial dysfunction and intracellular calcium dysregulation in ALS

Abstract

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder that affects the aging population. A progressive loss of motor neurons in the spinal cord and brain leads to muscle paralysis and death. As in other common neurodegenerative diseases, aging-related mitochondrial dysfunction is increasingly being considered among the pathogenic factors. Mitochondria are critical for cell survival: they provide energy to the cell, buffer intracellular calcium, and regulate apoptotic cell death. Whether mitochondrial abnormalities are a trigger or a consequence of the neurodegenerative process and the mechanisms whereby mitochondrial dysfunction contributes to disease are not clear yet. Calcium homeostasis is a major function of mitochondria in neurons, and there is ample evidence that intracellular calcium is dysregulated in ALS. The impact of mitochondrial dysfunction on intracellular calcium homeostasis and its role in motor neuron demise are intriguing issues that warrants in depth discussion. Clearly, unraveling the causal relationship between mitochondrial dysfunction, calcium dysregulation, and neuronal death is critical for the understanding of ALS pathogenesis. In this review, we will outline the current knowledge of various aspects of mitochondrial dysfunction in ALS, with a special emphasis on the role of these abnormalities on intracellular calcium handling.

Genetic variability of the gene cluster CALHM1–3 in sporadic Creutzfeldt-Jakob disease

“…Perturbations of calcium regulation has been described in several neurodegenerative disorders, such as Alzheimer (AD), amyotrophic lateral sclerosis, Parkinson, Huntington and prion diseases. [1][2][3][4][5][6][7][8][9][10][11] In 2008, Dreses-Werringloer and collaborators identified a polymorphism (rs2986017) associated with AD in the gene CALHM1 coding for a novel regulator of calcium homeostasis called CALHM1, which appears to be involved in the metabolism of amyloid β precursor protein (APP). 12 Although some authors have failed to confirm these results, a meta-analysis has shown that this polymorphism modulates the age at disease onset.…”

Mitochondrial Disorders May Mimic Amyotrophic Lateral Sclerosis at Onset

“…Hirano et al reported a 65-year-old ALS patient whose muscle biopsy showed 10% ragged- and alterations of the mitochondrial genome and transcriptome. [8][9][10][11][12][13][14] There are also indications that mtDNA deletions are more common in individuals with sporadic ALS as compared to healthy controls. 15 Mitochondrial dysfunction in ALS is often regarded as secondary following the exposure of mtDNA to increased oxidative stress.…”

Mitophagy and the therapeutic clearance of damaged mitochondria for neuroprotection

“…Indeed, overexpression of PGC1α in HD model mice, restored biogenesis and eliminated protein aggregates by activation of TFEB, a regulator of the autophagy-lysosome pathway (Tsunemi et al, 2012) Amyotrophic lateral sclerosis (ALS) is characterised by a progressive loss of motor neurons in the brain and spinal cord leading to fatal muscle paralysis (Kawamata and Manfredi, 2010). The specific causes of cell death are still under active investigation however several studies have implicated mutant superoxide dismutase SOD1, a key antioxidant enzyme, and TDP-43, a DNA binding protein, to mitochondrial dysfunction in ALS.…”