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Published on: January 7, 2019
Toxic gain of function from mutant FUS protein is crucial to trigger cell autonomous motor neuron loss
Jelena Scekic-Zahirovic1, Oliver Sendscheid2, Hajer El Oussini1
1Faculté de Médecine, INSERM U1118, Strasbourg, France Université de Strasbourg UMR_S1118, Strasbourg, France.
Abstract:
FUS is an RNA-binding protein involved in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Cytoplasmic FUS-containing aggregates are often associated with concomitant loss of nuclear FUS Whether loss of nuclear FUS function, gain of a cytoplasmic function, or a combination of both lead to neurodegeneration remains elusive. To address this question, we generated knockin mice expressing mislocalized cytoplasmic FUS and complete FUS knockout mice. Both mouse models display similar perinatal lethality with respiratory insufficiency, reduced body weight and length, and largely similar alterations in gene expression and mRNA splicing patterns, indicating that mislocalized FUS results in loss of its normal function. However, FUS knockin mice, but not FUS knockout mice, display reduced motor neuron numbers at birth, associated with enhanced motor neuron apoptosis, which can be rescued by cell-specific CRE-mediated expression of wild-type FUS within motor neurons. Together, our findings indicate that cytoplasmic FUS mislocalization not only leads to nuclear loss of function, but also triggers motor neuron death through a toxic gain of function within motor neurons.
Insights
Mislocalized FUS protein causes neurodegeneration in ALS and FTD by both losing its normal function and gaining toxic cytoplasmic function, leading to motor neuron death.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- FUS protein is implicated in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
- Cytoplasmic aggregates of FUS often correlate with reduced nuclear FUS levels.
- The precise mechanisms driving neurodegeneration, whether loss of nuclear function or gain of cytoplasmic function, remain unclear.
Purpose of the Study:
- To investigate the distinct roles of nuclear loss-of-function and cytoplasmic gain-of-function of FUS in neurodegeneration.
- To elucidate the mechanisms underlying FUS-associated neurodegenerative diseases.
Main Methods:
- Generation of knockin mice expressing cytoplasmic mislocalized FUS.
- Generation of complete FUS knockout mice.
- Comparative analysis of FUS knockin and knockout models for perinatal lethality, physiological defects, gene expression, mRNA splicing, and motor neuron apoptosis.
Main Results:
- Both FUS models exhibited perinatal lethality, respiratory issues, and altered gene expression/splicing, suggesting FUS mislocalization causes loss of normal function.
- FUS knockin mice, unlike knockout mice, showed reduced motor neuron numbers and increased apoptosis at birth.
- This motor neuron apoptosis in knockin mice was reversible with wild-type FUS expression in motor neurons.
Conclusions:
- Cytoplasmic FUS mislocalization leads to both loss of its essential nuclear functions and a toxic gain of function within motor neurons.
- This dual mechanism contributes to motor neuron degeneration observed in FUS-related neurodegenerative diseases.
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