Abstract:

Amyotrophic lateral sclerosis (ALS) is a lethal disorder characterized by the gradual degeneration of brainstem and spinal motoneurons as well as lateral cortico-spinal tracts. The onset generally occurs during the adult age except for some juvenile aggressive forms. Until recently, the vast majority of the cases (90%) were deemed sporadic. Mutations in the SOD1 gene have been for a long time the only ones reported in familiar forms of ALS. The recent implication of new genes of little known function cast a new view on this disease. C9ORF75, for example, is now recognized to account for 30% of the familial cases. Overall, ALS has been linked to 20 different genes, many also associated with other degenerative diseases (frontotemporal dementia, Alzheimer or ataxia). Some of these genes are involved in RNA maturation (FUS, TARBD). Clinical observation of human patients and mouse models suggest that all motor pools and motoneurons are not equally affected. The disease usually starts in motor pools controlling the limbs or in the bulbar area before expanding to other motor pools, with the exception of a few resistant ones (Onuf’s and oculomotor nuclei). Within a vulnerable motor pool, motoneurons subtypes also exhibit differential vulnerability and follow an orderly degeneration; starting with the motoneurons innervating fast-contracting fatigable motor units (FF motoneurons) and followed by the ones innervating fast-contractile fatigue-resistant motor units (FR motoneurons). The motoneurons innervating slow motor units (S motoneurons) appear resistant to the disease. Although the mechanisms leading to the orderly degeneration are not known, many hypotheses have been raised.