Calcium, mitochondria, and the pathogenesis of ALS: the good, the bad, and the ugly

Jaiswal, Manoj Kumar

doi:10.3389/fncel.2013.00199

Cited by 38 publications

(36 citation statements)

References 3 publications

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“…Many ALS patients demonstrate elevated extracellular glutamate levels in the spinal cord, and glutamate excitotoxicity has been implicated in the pathogenesis of both sALS and fALS (Rothstein, 1995 ; Bruijn et al, 2004 ; Jaiswal, 2013 ). We further employed rat primary spinal cord cultured motor neurons challenged with glutamate as a model to investigate the potential cause of Miro1 deficiency in sALS.…”

Section: Resultsmentioning

confidence: 99%

Miro1 deficiency in amyotrophic lateral sclerosis

Zhang

Wang

Siedlak

et al. 2015

Front. Aging Neurosci.

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Proper transportation of mitochondria to sites with high energy demands is critical for neuronal function and survival. Impaired mitochondrial movement has been repeatedly reported in motor neurons of amyotrophic lateral sclerosis (ALS) patients and indicated as an important mechanism contributing to motor neuron degeneration in ALS. Miro1, a RhoGTPase also referred to as Rhot1, is a key regulator of mitochondrial movement linking mitochondria and motor proteins. In this study, we investigated whether the expression of Miro1 was altered in ALS patients and ALS animal models. Immunoblot analysis revealed that Miro1 was significantly reduced in the spinal cord tissue of ALS patients. Consistently, the decreased expression of Miro1 was also noted only in the spinal cord, and not in the brain tissue of transgenic mice expressing ALS-associated SOD1 G93A or TDP-43 M337V. Glutamate excitotoxicity is one of the major pathophysiological mechanisms implicated in the pathogenesis of ALS, and we found that excessive glutamate challenge lead to significant reduction of Miro1 expression in spinal cord motor neurons both in vitro and in mice. Taken together, these findings show Miro1 deficiency in ALS patients and ALS animal models and suggest glutamate excitotoxicity as a likely cause of Miro1 deficiency.

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Section: Resultsmentioning

confidence: 99%

Miro1 deficiency in amyotrophic lateral sclerosis

Zhang

Wang

Siedlak

et al. 2015

Front. Aging Neurosci.

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“…Neurocalcin is a member of the highly homologous visinin-like protein (VSNL) subfamily of neuronal calcium sensor proteins [30]; other members of this family such as VILIP-1 are reduced in the brains of Alzheimer's patients [31]. More broadly, the dysregulation of calcium homeostasis has been implicated in a range of neurodegenerative diseases via complications related to energy metabolism and oxidative stress [32,33].…”

Section: Discussionmentioning

confidence: 99%

An initial top-down proteomic analysis of the standard cuprizone mouse model of multiple sclerosis

et al. 2015

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An initial proteomic analysis of the cuprizone mouse model to characterise the breadth of toxicity by assessing cortex, skeletal muscle, spleen and peripheral blood mononuclear cells. Cuprizone treated vs. control mice for an initial characterisation. Select tissues from each group were pooled, analysed in triplicate using two-dimensional gel electrophoresis (2DE) and deep imaging and altered protein species identified using liquid chromatography tandem mass spectrometry (LC/MS/MS). Forty-three proteins were found to be uniquely detectable or undetectable in the cuprizone treatment group across the tissues analysed. Protein species identified in the cortex may potentially be linked to axonal damage in this model, and those in the spleen and peripheral blood mononuclear cells to the minimal peripheral immune cell infiltration into the central nervous system during cuprizone mediated demyelination. Primary oligodendrocytosis has been observed in type III lesions in multiple sclerosis. However, the underlying mechanisms are poorly understood. Cuprizone treatment results in oligodendrocyte apoptosis and secondary demyelination. This initial analysis identified proteins likely related to axonal damage; these may link primary oligodendrocytosis and secondary axonal damage. Furthermore, this appears to be the first study of the cuprizone model to also identify alterations in the proteomes of skeletal muscle, spleen and peripheral blood mononuclear cells. Notably, protein disulphide isomerase was not detected in the cuprizone cohort; its absence has been linked to reduced major histocompatibility class I assembly and reduced antigen presentation. Overall, the results suggest that, like experimental autoimmune encephalomyelitis, results from the standard cuprizone model should be carefully considered relative to clinical multiple sclerosis.

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“…Many authors have studied abnormalities in calcium regulation by neurons and the resultant motor neuron toxicity, but no definite causal relationship has been established. 15,16 Generalized body pain, a predominant complaint in our patient, is among the early features of hypocalcemia. 17 Although body aches and pain have also been found to be associated with ALS, they are usually not a prominent clinical feature early in the disease course.…”

Section: Discussionmentioning

confidence: 75%

“…Changes of chronic denervation and reinnervation were seen in distal foot and leg muscles symmetrically and were much more likely secondary to longstanding neuropathy rather than the acute process causing the diffuse active denervation. Many authors have studied abnormalities in calcium regulation by neurons and the resultant motor neuron toxicity, but no definite causal relationship has been established …”

Section: Discussionmentioning

confidence: 99%