Proline/arginine dipeptide repeat polymers derail protein folding in amyotrophic lateral sclerosis

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases with shared clinical and pathological features.
• A common genetic cause is a C9orf72 gene hexanucleotide repeat expansion, leading to toxic dipeptide repeat polymers.
• Misfolded protein aggregates are a hallmark of these devastating conditions.

Purpose of the Study:

• To elucidate the molecular mechanism by which C9orf72-associated dipeptide repeat polymers cause neurodegeneration.
• To investigate the interaction between proline/arginine repeat polymers and molecular chaperones.
• To understand how these interactions contribute to protein homeostasis disruption.

Main Methods:

• Utilized Nuclear Magnetic Resonance (NMR) spectroscopy to study polymer-chaperone interactions.
• Employed X-ray crystallography to determine the atomic structure of the complex.
• Investigated the impact of proline/arginine polymers on the catalytic activity of prolyl isomerase (PPIA).

Main Results:

• Proline/arginine repeat polymers sequester molecular chaperones, specifically inhibiting the folding catalyst activity of PPIA.
• NMR and X-ray crystallography revealed that these polymers bind to the active site of PPIA.
• The study defined the atomic basis for the specific interactions between disease-associated polymers and PPIA.

Conclusions:

• Proline/arginine repeat polymers exert toxicity by directly interfering with the function of crucial molecular chaperones like PPIA.
• This specific mechanism of chaperone sequestration leads to derailed protein homeostasis in C9orf72-associated neurodegenerative diseases.
• The findings provide a molecular understanding of neurodegeneration in ALS and FTD caused by C9orf72 expansions.