ALS-Causing Protein TDP-43 Impairs SREBP2 Cholesterol Regulation

Abstract Dyslipidemia is correlated with the prognosis of amyotrophic lateral sclerosis (ALS), a fatal motor neuron disorder characterized pathologically by TAR DNA binding protein (TDP-43) inclusions. We investigated molecular mechanisms of lipid metabolism regulated by TDP-43 in ALS. Expression microarray and RNA deep sequencing (RNA-Seq) were performed using cell lines expressing doxycycline-inductive TDP-43. Gene expression and transcriptome profiling identified 434 significantly altered genes under high levels of TDP-43 (Tukey’s test, P < 0.05) including sterol regulatory element-binding protein 2 (SREBP2), a master regulator of cholesterol homeostasis and its downstream genes. TDP-43 overexpression impaired SREBP2 transcriptional activity, leading to inhibition of cholesterol biosynthesis via the nutrient- and growth factor-responsive kinase mTOR Complex I (mTORC1). The amount of cholesterol was significantly decreased in motor neuronal cultures derived from ALS-patient induced pluripotent stem cells (iPSCs) as well as in the spinal fluids of ALS patients and in the spinal cord of ALS model mice. Impairment of cholesterol synthesis is caused by an increase in toxic function of TDP-43 in ALS.