ALS-associated mutation FUS-R521C causes DNA damage and RNA splicing defects

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Autosomal dominant mutations in the RNA/DNA binding protein FUS are associated with familial amyotrophic lateral sclerosis (FALS).
• The precise mechanisms by which FUS mutations lead to neurodegeneration remain incompletely understood.

Purpose of the Study:

• To investigate the molecular mechanisms underlying neurodegeneration caused by FUS mutations.
• To identify specific neuronal targets affected by FUS mutations and their contribution to FALS pathogenesis.

Main Methods:

• Utilized transgenic mice expressing a common FALS-associated FUS mutation (FUS-R521C).
• Assessed DNA damage, dendritic and synaptic phenotypes, and gene expression (RNA-seq).
• Performed electrophoretic mobility shift assays to study FUS RNA interactions.

Main Results:

• Mutant FUS proteins formed stable complexes with wild-type FUS, interfering with FUS-HDAC1 interactions and causing DNA damage.
• FUS-R521C mice exhibited significant dendritic and synaptic deficits.
• Brain-derived neurotrophic factor (BDNF) was identified as a target, with mutations causing Bdnf splicing defects and impaired BDNF signaling.
• RNA-seq revealed additional transcriptional and splicing defects in genes regulating dendritic growth and synaptic function.

Conclusions:

• Gain-of-function FUS mutations disrupt normal FUS protein interactions, leading to DNA damage and aberrant RNA processing.
• Impaired BDNF signaling and other gene dysregulations contribute to the observed dendritic and synaptic phenotypes in FUS-related neurodegeneration.
• These findings provide crucial insights into the pathogenesis of FALS linked to FUS mutations.