Neuronal dysfunction caused by FUSR521G promotes ALS-associated phenotypes that are attenuated by NF-κB inhibition

Area of Science:

• Neuroscience
• Genetics
• Pathology

Background:

• Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are related neurodegenerative diseases sharing clinical, pathological, and genetic links.
• Fused in sarcoma (FUS) protein mutations are implicated in ALS/FTD, with existing models showing motor and cognitive deficits.
• The precise cell-autonomous role of FUS mutations in motor neuron structural changes and disease progression requires further elucidation.

Purpose of the Study:

• To investigate the cell-autonomous role of the ALS-linked FUS R521G variant in motor neuron dendritic and synaptic changes.
• To correlate these structural changes with ALS/FTD-associated phenotypes.
• To evaluate the therapeutic potential of inhibiting the NF-κB pathway in a FUS-mutant mouse model.

Main Methods:

• Generation of a neuron-specific FUS-transgenic mouse model (hFUS^R521G/Syn1) expressing the human FUSR521G variant.
• Longitudinal analysis of cognitive and motor functions, and neuromorphology of cortical and spinal motor neurons.
• Assessment of therapeutic effects of IMS-088, an NF-κB inhibitor, on disease phenotypes and pathology.

Main Results:

• Juvenile hFUS^R521G/Syn1 mice exhibited cognitive impairments and reduced cortical motor neuron dendritic branching, preceding motor deficits.
• Aged mice developed motor impairments, spinal motor neuron dendritic loss, FUS cytoplasmic mislocalization, mitochondrial abnormalities, and glial activation.
• IMS-088 treatment improved cognitive and motor function, increased dendritic branching and synapses, and attenuated pathological features, restoring mitochondrial function.

Conclusions:

• FUSR521G has a cell-autonomous role in initiating early dendritic and synaptic pathology in motor neurons, preceding overt motor deficits in ALS/FTD.
• Neuroinflammation, mediated by the NF-κB pathway, significantly contributes to neuronal dysfunction and disease progression.
• Modulation of the NF-κB pathway represents a promising therapeutic strategy for attenuating ALS/FTD progression.