Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition characterised by a progressive loss of motor neurons controlling voluntary muscle activity. The disease manifests through a variety of motor dysfunctions related to the extent of damage and loss of neurons at different anatomical locations. Despite extensive research, it remains unclear why some motor neurons are especially susceptible to the disease, while others are affected less or even spared. In this article, we review the neurobiological mechanisms, neurochemical profiles, and morpho-functional characteristics of various motor neuron groups and types of motor units implicated in their differential exposure to degeneration. We discuss specific cell-autonomous (intrinsic) and extrinsic factors influencing the vulnerability gradient of motor units and motor neuron types to ALS, with their impact on disease manifestation, course, and prognosis, as revealed in preclinical and clinical studies. We consider the outstanding challenges and emerging opportunities for interpreting the phenotypic and mechanistic variability of the disease to identify targets for clinical interventions.

Center of Biomedical Network Research on Mental Health ISCIII Madrid Spain

Department of Medical Genetics 3rd Faculty of Medicine Charles University Ruská 87 10000 Prague Czech Republic

Faculty of Engineering and Science University of Greenwich London Chatham Maritime Kent ME4 4TB UK

Instituto de Neurociencias UMH CSIC Avda Ramon y Cajal 03550 San Juan de Alicante Spain

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