ALS: A bucket of genes, environment, metabolism and unknown ingredients

• ALS: multiple pathogenic mechanisms that share TDP-43 deposits as common trait.
• Most of genes related to ALS are involved in RNA metabolism, endosome trafficking, autophagy and energy metabolism.
• C9ORF72 expansion plays a common role in sporadic and familiar ALS pathogenesis.
• ALS is a multi-system disease with important metabolic alterations.
• Genes, environment and toxins are key factors to unveil the enigma of motor neuron degeneration.

The scientific scenario of amyotrophic lateral sclerosis (ALS) has dramatically changed since TDP-43 aggregates were discovered in 2006 as the main component of the neuronal inclusions seen in the disease, and more recently, when the implication of C9ORF72 expansion in familial and sporadic cases of ALS and frontotemporal dementia was confirmed. These discoveries have enlarged an extense list of genes implicated in different cellular processes such as RNA processing or autophagia among others and have broaden the putative molecular targets of the disease. Some of ALS-related genes such as TARDBP or SOD1 among others have important roles in the regulation of glucose and fatty acids metabolism, so that an impairment of fatty acids (FA) consumption and ketogenic deficits during exercise in ALS patients would connect the physiopathology with some of the more intriguing epidemiological traits of the disease. The current understanding of ALS as part of a continuum with other neurodegenerative diseases and a crossroads between genetic, neurometabolic and environmental factors represent a fascinating model of interaction that could be translated to other neurodegenerative diseases. In this review we summarize the most relevant data obtained in the ten last years and the key lines for future research in ALS.