The precise contribution of endoplasmic reticulum (ER) chaperone protein disulfide isomerase (PDI) variants in human amyotrophic lateral sclerosis (ALS) patients to the pathogenesis of ALS remained unclear. In the present study, Woehlbier et al (2016) demonstrated that these PDI variants are capable of altering motor neuron morphology, impairing the expression of synaptic proteins, and compromising neuromuscular junction (NMJ) integrity.
See also: U Woehlbier et al
Amyotrophic lateral sclerosis (ALS) is an adult‐onset fast progressing fatal neurodegenerative disease characterized by the progressive degeneration of upper and lower motor neuron, paralysis, and muscle atrophy. While sporadic cases of ALS (sALS) (where the cause of ALS remains unknown) predominate, for some ALS cases, an inherited genetic defect has been implicated. The complexity of disease etiology is illustrated by the variety of mutated genes contributing to familial ALS (fALS) such as superoxide dismutase 1 (SOD1), TDP‐43, FUS, Ubiquilin‐2, and C9ORF72 (Turner et al, 2013). Thus, various pathogenic mechanisms associated with those mutations have been proposed involving protein misfolding and aggregation, defective RNA processing, endoplasmic reticulum (ER) and mitochondrial dysfunction, disruption of membrane trafficking, and glutamate excitotoxicity (reviewed in Peters et al, 2015). However, it has remained unclear whether any of these mechanisms are causally linked or consequential events secondary to protein misfolding induced cellular pathology. Recently, the identification of variants in two genes of the protein disulfide isomerase (PDI) …
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