RNA and the RNA-binding protein FUS act in concert to prevent TDP-43 spatial segregation

Area of Science:

• Neurobiology
• Molecular Biology
• Biochemistry

Background:

• Fused in sarcoma (FUS) and TAR DNA-binding protein 43 (TDP-43) are aggregation-prone proteins linked to neurodegeneration.
• Mutations in FUS and TDP-43 cause pathological cytoplasmic aggregation in neurons.
• Both proteins are involved in mRNA processing and form nuclear compartments.

Purpose of the Study:

• To investigate the interaction between FUS and TDP-43 in the context of neurodegeneration.
• To elucidate the mechanism of TDP-43 recruitment into FUS assemblies.
• To determine the role of mRNA in mediating the interaction between FUS and TDP-43.

Main Methods:

• In vitro high-resolution analyses.
• Cellular context studies.
• Investigation of wild-type and truncated TDP-43 (TDP-25) interactions with FUS.

Main Results:

• TDP-43 is specifically recruited into FUS assemblies, forming TDP-43-rich subcompartments.
• This recruitment is reciprocal, with FUS not being recruited into TDP-43 assemblies.
• mRNA presence promotes the mixing of TDP-43 and FUS.
• TDP-25, with impaired RNA-binding, fails to mix with FUS.

Conclusions:

• FUS binding to nascent mRNAs facilitates the mixing of aggregation-prone TDP-43 into FUS-rich phases.
• This interaction forms distinct mRNA-rich subcompartments.
• A functional link between FUS and TDP-43, mediated by RNA, may explain their co-implication in amyotrophic lateral sclerosis.