Molecular Investigations of Protein Aggregation in the Pathogenesis of Amyotrophic Lateral Sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a devastating progressive neurodegenerative disorder characterized by selective loss of lower and upper motor neurons (MNs) in the brain and spinal cord, resulting in paralysis and eventually death due to respiratory insufficiency. Although the fundamental physiological mechanisms underlying ALS are not completely understood, the key neuropathological hallmarks of ALS pathology are the aggregation and accumulation of ubiquitinated protein inclusions within the cytoplasm of degenerating MNs. Herein, we discuss recent insights into the molecular mechanisms that lead to the accumulation of protein aggregates in ALS. This will contribute to a better understanding of the pathophysiology of the disease and may open novel avenues for the development of therapeutic strategies.

Keywords: aggregation; amyotrophic lateral sclerosis; neurodegenerative diseases.

Figure 1

The pathways involved in protein aggregation in neuronal cells, leading to neuronal death typically found in neurodegenerative diseases.

Figure 2

Structures and functional domains of SOD1, TDP-43, and FUS proteins.

Figure 3

The protein aggregates typically associated with ALS are linked to protein inclusions in other neurodegenerative diseases, also promoting neuronal death in these pathologies.