Discovery and Exploration of Lipid-Modifying Drug Targets for ALS by Mendelian Randomization.

Observational studies have faced challenges in identifying replicable causes for amyotrophic lateral sclerosis (ALS). To address this, we employed an unbiased and data-driven approach to discover and explore potential causal exposures using two-sample Mendelian randomization (MR) analyses. In the phenotype discovery stage, we assessed 3948 environmental exposures from the UK Biobank and utilized ALS summary statistics (Europeans, 20,806 cases, 59,804 controls) as the outcome within a phenome-wide MR pipeline. Through a range of sensitivity analyses, two medication traits were identified to be protective for ALS. In the target exploration stage, we further conducted drug target MR analyses using the latest and trans-ethnic summary data on lipid-related traits and ALS (Europeans, 27,205 cases, 110,881 controls; East Asians, 1234 cases, 2850 controls). Our aim was to explore potential causal drug targets through six lipid-modifying effects. These comprehensive analyses revealed significant findings. Specifically, "cholesterol-lowering medication" and "atorvastatin" survived predefined criteria in the phenotype discovery stage and exhibited a protective effect on ALS. Further in the target exploration stage, we demonstrated that the therapeutic effect of APOB through LDL-lowering was associated with reduced ALS liability in Europeans (OR = 0.835, P = 5.61E - 5). Additionally, the therapeutic effect of APOA1 and LDLR through TC-lowering was associated with reduced ALS liability in East Asians (APOA1, OR = 0.859, P = 5.38E - 4; LDLR, OR = 0.910, P = 2.73E - 5). Overall, we propose potential protective effects of cholesterol-lowering drugs or statins on ALS risk from thousands of exposures. Our research also suggests APOB, APOA1, and LDLR as novel therapeutic targets for ALS and supports their potential protective mechanisms may be mediated by LDL-lowering or TC-lowering effects.

Loss of CHCHD2 Stability Coordinates with C1QBP/CHCHD2/CHCHD10 Complex Impairment to Mediate PD-Linked Mitochondrial Dysfunction.

Novel CHCHD2 mutations causing C-terminal truncation and interrupted CHCHD2 protein stability in Parkinson's disease (PD) patients were previously found. However, there is limited understanding of the underlying mechanism and impact of subsequent CHCHD2 loss-of-function on PD pathogenesis. The current study further identified the crucial motif (aa125-133) responsible for diminished CHCHD2 expression and the molecular interplay within the C1QBP/CHCHD2/CHCHD10 complex to regulate mitochondrial functions. Specifically, CHCHD2 deficiency led to decreased neural cell viability and mitochondrial structural and functional impairments, paralleling the upregulation of autophagy under cellular stresses. Meanwhile, as a binding partner of CHCHD2, C1QBP was found to regulate the stability of CHCHD2 and CHCHD10 proteins to maintain the integrity of the C1QBP/CHCHD2/CHCHD10 complex. Moreover, C1QBP-silenced neural cells displayed severe cell death phenotype along with mitochondrial damage that initiated a significant mitophagy process. Taken together, the evidence obtained from our in vitro and in vivo studies emphasized the critical role of CHCHD2 in regulating mitochondria functions via coordination among CHCHD2, CHCHD10, and C1QBP, suggesting the potential mechanism by which CHCHD2 function loss takes part in the progression of neurodegenerative diseases.