Dysfunction of autophagy as the pathological mechanism of motor neuron disease based on a patient-specific disease model.

Autophagy is the main catabolic pathway in cells for the degradation of impaired proteins and organelles. Accumulating evidence supports the hypothesis that dysfunction of autophagy, leading to an imbalance of proteostasis and the accumulation of toxic proteins in neurons, is a central player in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS). The clinical pathology of ALS is complex and many genes associated with autophagy and RNA processing are mutated in patients with the familial form. But a causal relationship between autophagic dysfunction and ALS has not been fully established. More importantly, studies on the pathological mechanism of ALS are mainly based on animal models that may not precisely recapitulate the disease itself in human beings. The development of human iPSC techniques allows us to address these issues directly in human cell models that may profoundly influence drug discovery for ALS.