Microprotein Regulates G-quadruplex Driven RNA Aggregation

Area of Science:

• Molecular Biology
• Neuroscience
• Biochemistry

Background:

• Hexanucleotide repeat expansions in C9orf72 are implicated in Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD).
• These expansions lead to aberrant RNA phase transitions, involving structures like G-quadruplexes, contributing to disease pathogenesis.
• The role of specific regulatory proteins in modulating these RNA structures and phase behaviors remains an active area of investigation.

Purpose of the Study:

• To investigate the function of the human microprotein ZNF706 in regulating RNA phase transitions driven by hexanucleotide repeats.
• To determine if ZNF706 can modulate G-quadruplex formation and the subsequent phase behavior of repeat RNAs.
• To elucidate the potential therapeutic implications of ZNF706 in the context of C9orf72-linked neurodegenerative diseases.

Main Methods:

• Investigated ZNF706's effect on G-quadruplex formation using biophysical assays.
• Assessed ZNF706's impact on RNA phase behavior and aggregate formation in cellular models.
• Quantified the production and clearance of dipeptide repeat proteins in cells with altered ZNF706 levels.
• Analyzed the influence of ZNF706 on the viscoelastic properties of RNA condensates.

Main Results:

• ZNF706 antagonizes pathological gel-solid transitions by melting hexanucleotide repeat G-quadruplex structures.
• ZNF706 converts gel-like aggregates into more dynamic condensates, influencing condensate fluidity and viscoelasticity.
• Loss of ZNF706 enhances cellular clearance of dipeptide repeat proteins, while overexpression suppresses their production and promotes clearance.
• ZNF706 functions as an RNA chaperone, remodeling repeat RNA structures and solubilizing RNA aggregates.

Conclusions:

• ZNF706 acts as a key regulator of G-quadruplex formation and RNA phase behavior.
• ZNF706's RNA chaperone activity offers a mechanism to counteract pathological RNA aggregation in C9orf72-linked neurodegenerative diseases.
• Targeting ZNF706 or its pathway may represent a novel therapeutic strategy for ALS and FTD.