PolyQ-expanded ataxin-2 aggregation impairs cellular processing-body homeostasis via sequestering the RNA helicase DDX6

Area of Science:

• Molecular Biology
• Neuroscience
• RNA Biology

Background:

• Ataxin-2 (Atx2) is an RNA-binding protein with a polyglutamine (polyQ) tract.
• PolyQ expansion in Atx2 can lead to protein aggregation, implicated in neurodegenerative diseases like spinocerebellar ataxia type 2 (SCA2).
• The precise mechanism by which Atx2 aggregation contributes to neurodegeneration is not fully understood.

Purpose of the Study:

• To investigate how Atx2 aggregation influences the assembly and function of cellular processing bodies (P-bodies).
• To elucidate the molecular interactions and consequences of Atx2 aggregation on RNA metabolism and P-body homeostasis.

Main Methods:

• Biochemical assays
• Fluorescence imaging techniques
• Analysis of protein-RNA interactions and cellular localization.

Main Results:

• PolyQ-expanded (PQE) Atx2 sequesters the DEAD-box RNA helicase (DDX6) into aggregates, mediated by specific RNA sequences.
• The N-terminal LSm domain of Atx2 and the C-terminal helicase domain of DDX6 are crucial for this interaction.
• DDX6 sequestration disrupts P-body assembly, leading to the release of MARF1, promoting mRNA decay and translational repression.
• Restoring DDX6 levels rescues P-body assembly and function, preventing mRNA degradation.

Conclusions:

• Atx2 aggregation impairs P-body homeostasis by sequestering essential components like DDX6.
• This disruption of P-body function contributes to dysregulated RNA metabolism, relevant to neurodegenerative disease pathologies.
• Targeting DDX6 sequestration or restoring P-body function presents a potential therapeutic strategy for related proteinopathies.