Conclusion
Motor neurons are unique cells compared to other neurons. They are large cells, with extraordinarily long axons, and very high energetic requirements, which may render them uniquely susceptible to degeneration in ALS. Remarkably, however, not all MNs are equally affected, and there are marked differences in vulnerabilities between MN subtypes, even within the same motor unit. The resistant MNs possess distinct morphological and functional characteristics, as well as different gene expression profiles, compared to the more vulnerable groups (Figure 4). Importantly, the oculomotor neurons continue to function, even in the late stages of ALS when the vulnerable spinal and other MNs are significantly depleted. These oculomotor neurons are anatomically and functionally very different from all other motor units: they are much smaller, and their function involves sensing rather than movement, hence different circuits are involved. In contrast, spinal MNs are more prone to hyperexcitation and they express high levels of AMPA receptors, they are more prone to develop ER stress, and they do not buffer Ca2+ as well as the more resistant MN types. These properties may confer unique sensitivity to neurodegeneration in ALS. Interestingly, even within spinal MNs, there are distinct differences in vulnerability, because FF-MNs degenerate first, followed by FR-MNs, and the more resistant S-MNs degenerate later. Similarly, these cells also display differences in excitability and ER stress.
FIGURE 4  Reported differences between the vulnerable (ventral spinal cord MNs) and resistant (oculomotor) motor neurons in ALS. The surface area and axonal conduction velocities referred to here were obtained from studies in cats (Westbury, 1982). The α-MNs innervate highly contracting extrafusal fibers, whereas γ-MNs innervate intrafusal fibers that contract much less; oculomotor neurons innervate the extraocular muscles in the orbit. α-MNs are larger than γ-MNs and oculomotor neurons and possess more dendritic trees. α-MNs are further subdivided based on their size and function. The proteins listed at the bottom of the figure are those enriched in each MN population. A hypothetical model is presented in Figure 5, summarizing the possible molecular mechanisms involved in MN vulnerability in ALS. The regulation of synaptic plasticity and neuronal excitability may underlie susceptibility in ALS involving nuclear-cytoplasmic defects, ER stress, transport dysfunction and mitochondrial alterations. From an initial site of onset, neurodegeneration begins in susceptible MN groups, and then spreads contiguously throughout the neuroanatomy, in a defined pattern, to the surrounding cells. This therefore highlights the role of impaired neurotransmission in triggering and propagating neurodegeneration in ALS. Glial cells are involved in both the onset and progression of ALS.
FIGURE 5  Diagram showing a hypothetic cascade of cellular events leading to neurodegeneration and neuronal death in motor neurons in ALS/FTD. This schematic diagram summarizes the key features occurring in vulnerable MNs. Resistant MNs are protected by the expression of a genes controlling cellular mechanisms that are defective in ALS/FTD (RNA dysfunction, ER stress, mitochondrial defects, protein transport dysfunction, dysregulation of neuronal excitability and excitotoxicity). These processes can be exacerbated by age, environmental and genetic mutations. The susceptibility of specific MN groups, however, is further complicated by the heterogeneous nature of ALS, even within the same families, and the different patterns of motor involvement. Stratification of ALS patients into distinct subtypes and investigations into MNs susceptibilities may reveal more insights why specific groups of MNs degenerate first in ALS in the future. However, the blurring of some neurodegenerative disorders, including ALS and FTD, and the presence of C9orf72 mutations in several other neurodegenerative conditions as well as ALS, is another confounding factor. Understanding the fundamental mechanisms dictating MN vulnerability in ALS is central to our understanding of this devastating disorder. Hence, studies in this area may lead to novel therapeutic insights in the future.