Selective vulnerability of motor neuron types and functional groups to degeneration in amyotrophic lateral sclerosis: review of the neurobiological mechanisms and functional correlates

Abstract

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.

Axon length-dependent synapse loss is mediated by neuronal cytokine-induced glial phagocytosis

“…One particularly salient feature of NDDs is the anatomical complexity of affected cells: neurons with extensive projections are more prone to degeneration, and the severity of degenerative phenotypes often correlates with axon length. This length-dependency is best illustrated in neuropathies including Charcot-Marie-Tooth (CMT) disease, hereditary spastic paraplegia (HSP) and amyotrophic lateral sclerosis (ALS), which show length-dependent degeneration of peripheral axons typically starting in distally innervated regions of the body (4)(5)(6)(7)(8). Similarly, peripheral neuropathy in some forms of spinocerebellar ataxia (SCA) involves length-dependent axonopathy (9)(10)(11).…”

Potential contribution of spinal interneurons to the etiopathogenesis of amyotrophic lateral sclerosis

“…In contrast, the most vulnerable MN types in ALS are somatic MNs that innervate fast-twitch fatigable (FF) muscle fibers (Pun et al, 2002 ; Wootz et al, 2013 ; Sharma et al, 2016 ; Spiller et al, 2016 ). The differential vulnerability of MN subtypes to ALS can be linked to several intrinsic or extrinsic factors such as soma or dendritic tree size, intracellular calcium dynamics, and excitatory/inhibitory synaptic inputs (Nijssen et al, 2017 ; Ovsepian et al, 2024 ).…”