Exploring Protein Misfolding in Amyotrophic Lateral Sclerosis: Structural and Functional Insights

Abstract

Protein functionality depends on its proper folding, making protein misfolding crucial for the function of proteins and, by extension, cells and the whole organism. Increasing evidence supports the role of protein misfolding in the pathogenesis of neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS). ALS is a rapidly progressive disease diagnosed at a prevalence of 5 cases per 100,000, with approximately 2-3 patients per 100,000 diagnosed each year. To date, there is no cure, and the disease usually leads to death within 2 to 5 years from diagnosis. There are two types of the disorder: familial ALS (fALS), accounting for approximately 10% of cases, and sporadic (sALS), accounting for the remaining 90%. The hallmark of ALS, regardless of type, is the protein aggregates found in patients' tissues. This suggests that the disruption of proteostasis plays a critical role in the development of the disease. Herein, we stress the distinct factors that lead to protein misfolding and aggregate formation in ALS. Specifically, we highlight several triggering factors affecting protein misfolding, namely mutations, errors in the processes of protein production and trafficking, and failures of folding and chaperone machinery. Gaining a deeper understanding of protein aggregation will improve our comprehension of disease pathogenesis and potentially uncover new therapeutic approaches.

Keywords: aggregation; amyotrophic lateral sclerosis; mutations; prion; protein misfolding; superoxide dismutase 1.

Figure 1

SOD1 protein trafficking at the Golgi apparatus. (A) Normally folded SOD1 and protein transport from the ER to the Golgi. (B) Different mutations in SOD1 affect protein trafficking at the Golgi in different ways. The ALS-associated mutations SOD1A4V, SOD1G85R, and SOD1G93A disrupt the secretory pathway, while the SOD1A4V mutation triggers the accumulation of secretory proteins and apoptosis.

Figure 2

The mechanisms through which ALS-associated aggregates impact protein folding machinery. (A) Mutants TDP-43 and FUS tend to aggregate and undergo ubiquitination, leading to a significant reduction in free ubiquitins. (B) TDP-25 binds proteasome subunits, preventing them from undergoing the conformational changes necessary for enzymatic activity. (C) SOD1 aggregates incorporate Hsc70, which protects SOD1 aggregates from proteasomal degradation. (D) ALS-linked mutant protein aggregates often bind and integrate chaperones, diminishing their active potential.

Figure 3

A summarized figure that recapitulates the main points of the present work emphasizing protein misfolding, aggregation, and dysfunctions in ALS.