Abstract
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the death of both upper and lower motor neurons (MNs) in the brain, brainstem and spinal cord. The neurodegenerative mechanisms leading to MN loss in ALS are not fully understood. Importantly, the reasons why MNs are specifically targeted in this disorder are unclear, when the proteins associated genetically or pathologically with ALS are expressed ubiquitously. Furthermore, MNs themselves are not affected equally; specific MNs subpopulations are more susceptible than others in both animal models and human patients. Corticospinal MNs and lower somatic MNs, which innervate voluntary muscles, degenerate more readily than specific subgroups of lower MNs, which remain resistant to degeneration, reflecting the clinical manifestations of ALS. In this review, we discuss the possible factors intrinsic to MNs that render them uniquely susceptible to neurodegeneration in ALS. We also speculate why some MN subpopulations are more vulnerable than others, focusing on both their molecular and physiological properties. Finally, we review the anatomical network and neuronal microenvironment as determinants of MN subtype vulnerability and hence the progression of ALS.
Highlights
Amyotrophic lateral sclerosis (ALS) is a late-onset, progressive and fatal neurodegenerative disease which primarily affects motor neurons (MNs) of the motor cortex of the brain, brainstem motor nuclei and anterior horn of the spinal cord (Kiernan et al, 2011; Renton et al, 2014; Al Sultan et al, 2016; Taylor et al, 2016)
We address several unanswered questions regarding the unique susceptibility of specific types of MNs in ALS: Why does neurodegeneration spread throughout specific neural networks? How can ubiquitously expressed genes be selectively toxic to MNs? Why are some MN subtypes more vulnerable to degeneration than others? We discuss the role of the neuronal network and the specific cellular microenvironment in driving cell-to-cell disease progression, plus the importance of genetics in influencing susceptibility of specific neuronal subpopulations
In FUSP525L and FUSR521C mouse models, no significant MN loss was detected in oculomotor neurons, whereas spinal cord MNs were progressively lost during disease course (Sharma et al, 2016)
Summary
Amyotrophic lateral sclerosis (ALS) is a late-onset, progressive and fatal neurodegenerative disease which primarily affects motor neurons (MNs) of the motor cortex of the brain, brainstem motor nuclei and anterior horn of the spinal cord (Kiernan et al, 2011; Renton et al, 2014; Al Sultan et al, 2016; Taylor et al, 2016). This involves specialized UMNs located in layer V of this region (Broadman area 4), the giant Betz cells or corticospinal MNs. These MNs are the cortical components of the MN circuit that initiates and Target muscle fiber Soma size Axon diameter Dendrite branching Motor unit size (innervation ratio) Membrane input resistance Firing Axon conduction velocity Afterhyperpolarization duration Recruitment Affected in ALS Affected in aging Markers
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