Abstract
Although we know that amyotrophic lateral sclerosis (ALS) is correlated with the glutamate-mediated corticomotor neuronal hyperexcitability, detailed ALS pathology remains largely unexplained. While a number of drugs have been developed, no cure exists so far. Here, we propose a hypothesis of neuronal cell death—incomplete autophagy positive-feedback loop—and summarize the role of the neuron-astrocyte glutamate-glutamine cycle in ALS. The disruption of these two cycles might ideally retard ALS progression. Cerebrovascular injuries (such as multiple embolization sessions and strokes) induce neuronal cell death and the subsequent autophagy. ALS impairs autophagosome-lysosome fusion and leads to magnified cell death. Trehalose rescues this impaired fusion step, significantly delaying the onset of the disease, although it does not affect the duration of the disease. Therefore, trehalose might be a prophylactic drug for ALS. Given that a major part of neuronal glutamate is converted from glutamine through neuronal glutaminase (GA), GA inhibitors may decrease the neuronal glutamate accumulation, and, therefore, might be therapeutic ALS drugs. Of these, Ebselen is the most promising one with strong antioxidant properties.
Highlights
Amyotrophic lateral sclerosis (ALS) symptoms are characterized by concomitant upper and lower motor neuron signs, with inexorable disease progression (Geevasinga et al, 2016)
Eisen et al (1992) proposed the primacy of corticomotor neurons in what has come to be known as the dying-forward hypothesis of amyotrophic lateral sclerosis (ALS) pathogenesis, which states that ALS begins centrally, with anterior horn cell degeneration mediated by corticomotor neuronal hyperexcitability via the trans-synaptic glutamate-mediated excitotoxic processes
The impairment in autophagosomelysosome fusion can be mimicked by bafilomycin A1 treatment (Ejlerskov et al, 2013), so if ALS onset was observed in the bafilomycin-A1-treated stroke model mice (Chen et al, 2015) at the convalescent period, these correlations would be confirmed
Summary
Amyotrophic lateral sclerosis (ALS) symptoms are characterized by concomitant upper and lower motor neuron signs, with inexorable disease progression (Geevasinga et al, 2016). Atypical ALS phenotypes are characterized by either merely upper motor neuron dysfunction (named primary lateral sclerosis, PLS) or lower motor neuronal signs encompassing flail leg and flail arm syndromes (named progressive muscular atrophy, PMA; Kiernan et al, 2011). Cortical dysfunction has been identified as an intrinsic feature of most ALS cases, suggesting that the dying-forward mechanism is the most important in the atypical ALS phenotypes (Vucic et al, 2013b). Riluzole can only slow down the progression of ALS; the drug cannot stop it (Vucic et al, 2013a)
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