Cysteine Modifications in the Pathogenesis of ALS

Area of Science:

• Neuroscience
• Biochemistry
• Molecular Biology

Background:

• Amyotrophic lateral sclerosis (ALS) involves misfolded and aggregated proteins like SOD1, TDP-43, and FUS/TLS.
• Diverse protein inclusions are observed in both sporadic and genetic ALS forms.
• A common underlying mechanism for these varied inclusions remains elusive.

Purpose of the Study:

• To review evidence linking cysteine modifications to protein aggregation in ALS.
• To explore the potential role of cysteine residue aberrations in ALS pathogenesis.
• To identify a unifying mechanism for diverse protein inclusions in ALS.

Main Methods:

• Literature review of studies on protein aggregation in ALS.
• Analysis of the role of cysteine residues in protein folding and aggregation.
• Examination of cysteine thiol homeostasis factors in ALS.

Main Results:

• Cysteine residues are critical for the aggregation of SOD1 and TDP-43.
• Disturbances in protein thiol homeostasis (e.g., PDI, glutathione, oxidation, palmitoylation) may affect cysteine proteostasis.
• Cysteine modifications are implicated in the formation of diverse protein inclusions.

Conclusions:

• Cysteine modifications represent a potential common mechanism in ALS pathogenesis.
• Aberrant cysteine proteostasis could explain the diverse protein aggregates observed in ALS.
• Targeting cysteine modifications may offer therapeutic strategies for ALS.