Early lethality and neuronal proteinopathy in mice expressing cytoplasm-targeted FUS that lacks the RNA recognition...

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Mutations in the fused in sarcoma (FUS) gene are found in approximately 5% of familial amyotrophic lateral sclerosis (ALS) cases.
• FUS-positive cytoplasmic inclusions are a common pathological hallmark in ALS patients with FUS mutations.
• The precise mechanisms by which FUS-RNA interactions in the cytoplasm influence its aggregation and contribute to ALS pathogenesis remain unclear.

Purpose of the Study:

• To investigate how altering FUS's RNA-binding specificity affects its cytoplasmic aggregation and in vivo disease manifestation.
• To characterize the phenotype and neuropathology of transgenic mice expressing a cytoplasm-localized FUS mutant lacking its RNA recognition motif (RRM).

Main Methods:

• Generation of transgenic mice expressing a cytoplasm-localized FUS isoform (FUS ΔRRMcyt) with an ALS-associated R522G mutation and lacking the RRM.
• Phenotypic assessment including observation of motor deficits and survival rates.
• Histological examination of FUS inclusions, neuronal loss, and neuroinflammation in the brains of affected mice.

Main Results:

• Neuronal expression of FUS ΔRRMcyt led to early lethality in mice, often preceded by severe tremors.
• Widespread FUS-positive cytoplasmic inclusions were observed in the neurons of transgenic mice.
• Despite extensive proteinopathy and severe phenotype, no significant neuronal loss or neuroinflammatory response was detected.

Conclusions:

• Altering FUS's interaction with RNA in vivo by removing the RRM can augment its cytoplasmic aggregation.
• The observed FUS proteinopathy and severe phenotype suggest that impaired RNA interactions contribute to the severity of FUS-associated neurodegenerative processes.
• These findings highlight the critical role of FUS-RNA interactions in preventing cytoplasmic aggregation and mitigating ALS-like pathology.