Abstract
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that cannot be slowed substantially using any currently-available clinical tools. Through decades of studying sporadic and familial ALS (SALS and FALS), researchers are coming to understand ALS as a complex syndrome with diverse genetic and environmental etiologies. It is know appreciated that motor neuron degeneration in ALS requires active (gain of function) and passive (loss of function) events to occur in non-neuronal cells, especially astrocytes and microglia. These neuroinflammatory processes produce paracrine factors that detrimentally affect motor neurons, precipitating protein aggregation and compromising cytoskeletal integrity. The result is a loss of neuronal homeostasis and progressive die-back of motor axons culminating in death of the afflicted motor neurons. This review will discuss experimental therapeutics that have been tested in murine ALS models, with an emphasis on those that have progressed to human clinical trials. Reasons will be considered for the frequent failure of preclinical successes to translate into positive clinical outcomes. Finally, this review will explore current trends in experimental therapeutics for ALS with emphasis on the emerging interest in axon guidance signaling pathways as novel targets for pharmacological support of neural cytoskeletal structure and function in order to slow ALS.
Highlights
Amyotrophic lateral sclerosis (ALS; colloquially referred to as Lou Gehrig’s disease in American English and Motor Neurone Disease in British English) is one member of a family of anterior horn diseases that cause progressive, irreversible degeneration and death of spinal motor neurons and their cortical efferents [1]
ALS is anatomically distinguished from other anterior horn diseases and motor neuropathologies by involvement of both upper and lower motor tracts with a relative sparing of sensory neural degeneration, though sensory involvement is present in a subset of ALS patients
It may be significant that most of the Mendelian factors associated with FALS code for proteins involved in cellular mass transport, or else code for proteins whose malfunction results in macromolecular aggregates that could impede these transport processes
Summary
It is know appreciated that motor neuron degeneration in ALS requires active (gain of function) and passive (loss of function) events to occur in non-neuronal cells, especially astrocytes and microglia. These neuroinflammatory processes produce paracrine factors that detrimentally affect motor neurons, precipitating protein aggregation and compromising cytoskeletal integrity. This review will discuss experimental therapeutics that have been tested in murine ALS models, with an emphasis on those that have progressed to human clinical trials.
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