Activity-dependent FUS dysregulation disrupts synaptic homeostasis

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• The RNA-binding protein fused-in-sarcoma (FUS) is implicated in neurodegenerative diseases like amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD).
• Both FUS mutations and overexpression of wild-type FUS can lead to disease pathogenesis in humans.

Purpose of the Study:

• To investigate the molecular and cellular mechanisms underlying FUS-associated neurodegenerative diseases.
• To create and characterize novel transgenic mouse models expressing wild-type (FUS(WT)) and mutant (FUS(R521G)) human FUS protein.

Main Methods:

• Generation of transgenic mice globally expressing low levels of human FUS(WT) and FUS(R521G).
• Phenotypic analysis including motor function, neuroinflammation, neuromuscular junction integrity, and survival rates.
• Assessment of dendritic arborization and spine density in FUS(R521G) 'escaper' mice.
• Biochemical analysis of FUS protein levels in response to metabotropic glutamate receptor activation.

Main Results:

• Both FUS(WT) and FUS(R521G) mice exhibit motor deficits, neuroinflammation, denervated neuromuscular junctions, and premature death, mimicking human ALS/FTLD.
• FUS(R521G) 'escaper' mice show reduced motor function, altered sociability, and decreased dendritic arbors and spines, unlike FUS(WT) mice.
• Activation of metabotropic glutamate receptors differentially affects FUS(R521G) and FUS(WT)/endogenous FUS protein levels, potentially explaining dendritic defects.

Conclusions:

• Transgenic mouse models expressing FUS(WT) and FUS(R521G) effectively recapitulate key features of FUS-associated neurodegenerative disorders.
• The FUS(R521G) mutation specifically induces dendritic spine abnormalities, suggesting distinct pathogenic mechanisms compared to FUS overexpression alone.
• Differential regulation of FUS protein by glutamate receptor signaling may contribute to the observed synaptic pathology in FUS(R521G) mice.