The debilitating neurologic disease familial amyotrophic lateral sclerosis (FALS), commonly known a Lou Gehrig’s disease, has been linked to mutations in several different genes, including the gene encoding the DNA/RNA binding protein FUS. Haiyan Qiu, Sebum Lee and colleagues developed a transgenic mouse model of FUS-associated FALS to examine how mutated FUS promotes FALS pathogenesis. FUS-R521C mice exhibited phenotypes similar to patients, including neurological dysfunction and pronounced DNA damage. The authors identified the brain-derived neurotrophic factor (Bdnf), a nerve growth factor that promotes dendritic growth and synaptic function, as a target of mutant FUS. Treatment of FUS-R521C neurons with BNDF only partially restored dendrite function, suggesting that FUS-R521C disrupts other factors required for neuron function. Evaluation of spinal cords from FUS-R521C revealed that there were multiple defects in the transcription and splicing of genes associated with dendrite growth and function as well as genes required for immune regulation. The accompanying image uses Golgi's method of silver impregnation to highlight the reduced dendritic arborization in the spinal motor neurons of a 1 month-old FUS-R521C transgenic mouse.
Autosomal dominant mutations of the RNA/DNA binding protein FUS are linked to familial amyotrophic lateral sclerosis (FALS); however, it is not clear how FUS mutations cause neurodegeneration. Using transgenic mice expressing a common FALS-associated FUS mutation (FUS-R521C mice), we found that mutant FUS proteins formed a stable complex with WT FUS proteins and interfered with the normal interactions between FUS and histone deacetylase 1 (HDAC1). Consequently, FUS-R521C mice exhibited evidence of DNA damage as well as profound dendritic and synaptic phenotypes in brain and spinal cord. To provide insights into these defects, we screened neural genes for nucleotide oxidation and identified brain-derived neurotrophic factor (
Haiyan Qiu ... Li-Huei Tsai, Eric J. Huang
Copyright © 2015 American Society for Clinical Investigation