Clinical Spectrum of Amyotrophic Lateral Sclerosis (ALS)

Abstract

Amyotrophic lateral sclerosis (ALS) is primarily characterized by progressive loss of motor neurons, although there is marked phenotypic heterogeneity between cases. Typical, or "classical," ALS is associated with simultaneous upper motor neuron (UMN) and lower motor neuron (LMN) involvement at disease onset, whereas atypical forms, such as primary lateral sclerosis and progressive muscular atrophy, have early and predominant involvement in the UMN and LMN, respectively. The varying phenotypes can be so distinctive that they would seem to have differing biology. Because the same phenotypes can have multiple causes, including different gene mutations, there may be multiple molecular mechanisms causing ALS, implying that the disease is a syndrome. Conversely, multiple phenotypes can be caused by a single gene mutation; thus, a single molecular mechanism could be compatible with clinical heterogeneity. The pathogenic mechanism(s) in ALS remain unknown, but active propagation of the pathology neuroanatomically is likely a primary component.

Figure 1.

Clinical pathology of ALS spreads in a contiguous and temporal fashion. In the healthy spinal cord (A), global neuronal integrity is intact. In the presymptomatic stage (B), dysfunction within motor neurons begins but remains local and does not yet translate to a clinical presentation. Subsequent neuronal degeneration and sequential spread of cellular dysfunction begin to have an effect on motor neuron function and result in early signs of symptoms (C). Neurotoxicity propagates from neuron to neuron and region to region, resulting in a cascade effect that ultimately destroys motor neurons regionally (D) and is transmitted to adjacent anatomical regions, ultimately resulting in systemic motor neuron dysfunction that presents as severe disease (E).

Figure 2.

Models of temporal-spatial progression in ALS. (A) Spatial spread begins at a focal point followed by sequential progression outward in space. (B) Summation and saturation occur when the sequential changes progress neuroanatomically in a postmitotic finite compartment such as the motor system. (C) The sequential changes progress temporally from molecular to cellular to neurophysiological and ultimately to clinical levels over time. (Figure adapted with permission from Ravits 2014.)

Figure 3.

Intermolecular and intercellular prion-like propagation of misfolded protein. Specific misfolded proteins have been shown to have prion-like propagated misfolding properties that may contribute to the contiguous spread of ALS pathology. For example, SOD1 misfolding can be induced by a variety of intracellular and extracellular stresses. Once a misfolded template is present, it can induce subsequent cycles of template-directed misfolding, converting neighboring SOD1 molecules into pathological isoforms, which can subsequently form oligomers and aggregates over time. Misfolded SOD1 can also accumulate in the ER–Golgi system, where it can enter the vesicle-mediated secretory pathway and exit the cell via secretion. Alternatively, large proteinaceous aggregates containing misfolded SOD1 are subsequently taken up by neighboring cells via macropinocytosis. (From Grad et al. 2015; adapted, with permission, from the authors.)