Supersaturated proteins in ALS.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by rapidly progressive degeneration of motor neurons in the brain and spinal cord. Although most forms of ALS are sporadic (sALS), ∼10% of cases are inherited in families (fALS). More than 50 ALS genes have been identified, with 16 of them unequivocally implicated in the pathogenesis (1). These genes function in a wide spectrum of cellular processes, which has posed a considerable challenge in understanding common genetic causes of ALS. Another major question in ALS, and neurodegeneration in general, is related to the selectivity of neuronal cell death. Why is toxicity of mutant genes detrimental to certain types of neuronal cells, while leaving others unaffected? In the case of ALS, motor neurons are selectively degenerated. In PNAS, Ciryam et al. (2) investigate the expression level relative to protein solubility for ALS-associated proteins. Their results indicate that these proteins, compared with the whole proteome, are “supersaturated.” Furthermore, coaggregating proteins in inclusion bodies appear to be significantly more supersaturated in motor neurons than in other tissue types. These findings provide a plausible explanation for two aspects of ALS pathology: genetic heterogeneity and motor neuron-specific toxicity.