Dipeptide repeat derived from C9orf72 hexanucleotide expansions forms amyloids or natively unfolded structures...

Area of Science:

• Neuroscience
• Genetics
• Biochemistry

Background:

• The C9orf72 hexanucleotide repeat expansion is the leading genetic cause of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD).
• Dipeptide Repeat Proteins (DPRs) produced from this repeat are implicated in disease pathogenesis due to their toxicity and aggregation in the brain.
• Understanding the structural properties of DPRs is crucial for elucidating their disease mechanisms.

Purpose of the Study:

• To characterize the structural features of three DPRs: poly-GA, poly-GP, and poly-PA.
• To investigate the in vitro aggregation properties of these DPRs.
• To determine the amyloid nature and dye-binding characteristics of poly-GA fibrils.

Main Methods:

• In vitro characterization of DPR structural properties.
• Analysis of fibril formation using biophysical techniques.
• Assessment of amyloid characteristics, including beta-sheet content and dye binding (Thioflavin T, Primuline).

Main Results:

• Dipeptide Repeat Proteins (DPRs) were found to be natively unstructured.
• Only poly-GA formed fibrillary aggregates in vitro.
• Poly-GA fibrils exhibited amyloid characteristics with high beta-sheet content but did not bind common amyloid dyes.
• The amyloid core of poly-GA fibrils did not encompass the entire primary structure.

Conclusions:

• Poly-GA fibrils possess amyloid properties distinct from those typically detected by standard amyloid dyes.
• The structural heterogeneity of DPR aggregation may influence their toxicity and deposition in neurodegenerative diseases.
• Further research into DPR structure-binding relationships is warranted to understand their role in ALS and FTD.