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.

CNS-derived extracellular vesicles from superoxide dismutase 1 (SOD1)G93A ALS mice originate from astrocytes and neurons and carry misfolded SOD1

“…In this light, it is interesting that SOD1 is a common EV marker, and future CNS vesicle studies in sporadic ALS may reveal misfolded SOD1, perhaps concentrated as a protective proteostatic cellular function. Our current findings on the baseline phenotype of mouse brain and spinal cord EVs may have bearing on the wider spectrum of ALS (70). The apparent significant enrichment of ribosome-associated proteins on the surface of only the ALS mouse model BDEV is reminiscent of the emerging consensus that dysregulation of translation is a hallmark of ALS and other neurodegenerative diseases like FTD (71,72).…”

Investigation of the intercellular transmission of α-synuclein, amyloid-β and TDP-43

“…Much like with other NDs, ALS patients often succumb to dysphagia, pneumonia or respiratory failure 105 . Unlike the other NDs discussed here, however, classical ALS patients rarely develop dementia, which is seen in patients with FTLD/ALS comorbidity (reviewed in 104,106 ). There is significant overlap in the symptoms and pathology of ALS and FTLD, leading to speculation that both of these disorders exist on a spectrum, differing mainly by the regions of the CNS that are afflicted 107 .…”

“…First described by Charles Bell in 1824 and in 1874 coined ALS by Jean-Martin Charcot, both Bell and Charcot detailed the motor disturbances that are now understood to be associated with the disease 102,103 . The initial symptoms of the disease include muscle weakness and atrophy, slurred speech and difficulty breathing or swallowing, eventually progressing to widespread motor deficits with patients losing the ability to use their hands and legs and inability to walk, speak and swallow (reviewed in 104 ). Much like with other NDs, ALS patients often succumb to dysphagia, pneumonia or respiratory failure 105 .…”

Defining the Neural Kinome: Strategies and Opportunities for Small Molecule Drug Discovery to Target Neurodegenerative Diseases

“…It is pathologically characterized by cytoplasmic inclusions of MNs primarily composed of ubiquitinated TDP-43 protein, except for patients with SOD1 or FUS mutations, in which case the main component of the inclusion bodies are SOD1 protein and FUS protein, respectively. 15 Clinical features of the disease are mainly associated with motor dysfunction (muscle weakness, spasticity, and atrophy), but almost half of patients also develop cognitive and/or behavioral symptoms. 15,16 Neuroinflammation has also been implicated in ALS as activated microglia and astrocytes are present in post-mortem tissue, and altered cytokine profiles have been reported.…”

“…15 Clinical features of the disease are mainly associated with motor dysfunction (muscle weakness, spasticity, and atrophy), but almost half of patients also develop cognitive and/or behavioral symptoms. 15,16 Neuroinflammation has also been implicated in ALS as activated microglia and astrocytes are present in post-mortem tissue, and altered cytokine profiles have been reported. 17…”