PolyGR and polyPR knock-in mice reveal a conserved neuroprotective extracellular matrix signature in C9orf72 ALS/FTD neurons.

Dipeptide repeat proteins are a major pathogenic feature of C9orf72 amyotrophic lateral sclerosis (C9ALS)/frontotemporal dementia (FTD) pathology, but their physiological impact has yet to be fully determined. Here we generated C9orf72 dipeptide repeat knock-in mouse models characterized by expression of 400 codon-optimized polyGR or polyPR repeats, and heterozygous C9orf72 reduction. (GR)400 and (PR)400 knock-in mice recapitulate key features of C9ALS/FTD, including cortical neuronal hyperexcitability, age-dependent spinal motor neuron loss and progressive motor dysfunction. Quantitative proteomics revealed an increase in extracellular matrix (ECM) proteins in (GR)400 and (PR)400 spinal cord, with the collagen COL6A1 the most increased protein. TGF-ß1 was one of the top predicted regulators of this ECM signature and polyGR expression in human induced pluripotent stem cell neurons was sufficient to induce TGF-ß1 followed by COL6A1. Knockdown of TGF-ß1 or COL6A1 orthologues in polyGR model Drosophila exacerbated neurodegeneration, while expression of TGF-ß1 or COL6A1 in induced pluripotent stem cell-derived motor neurons of patients with C9ALS/FTD protected against glutamate-induced cell death. Altogether, our findings reveal a neuroprotective and conserved ECM signature in C9ALS/FTD.

Exploring the Role of Plasma Lipids and Statin Interventions on Multiple Sclerosis Risk and Severity: A Mendelian Randomization Study.

BACKGROUND AND OBJECTIVES: There has been considerable interest in statins because of their pleiotropic effects beyond their lipid-lowering properties. Many of these pleiotropic effects are predominantly ascribed to Rho small guanosine triphosphatases (Rho GTPases) proteins. We aimed to genetically investigate the role of lipids and statin interventions on multiple sclerosis (MS) risk and severity. METHOD: We used two-sample Mendelian randomization (MR) to investigate (1) the causal role of genetically mimic both cholesterol-dependent (through low-density lipoprotein cholesterol (LDL-C) and cholesterol biosynthesis pathway) and cholesterol-independent (through Rho GTPases) effects of statins on MS risk and MS severity, (2) the causal link between lipids (high-density lipoprotein cholesterol [HDL-C] and triglycerides [TG]) levels and MS risk and severity, and (3) the reverse causation between lipid fractions and MS risk. We used summary statistics from the Global Lipids Genetics Consortium (GLGC), eQTLGen Consortium, and the International MS Genetics Consortium (IMSGC) for lipids, expression quantitative trait loci, and MS, respectively (GLGC: n = 188,577; eQTLGen: n = 31,684; IMSGC (MS risk): n = 41,505; IMSGC (MS severity): n = 7,069). RESULTS: The results of MR using the inverse-variance weighted method show that genetically predicted RAC2, a member of cholesterol-independent pathway (OR 0.86 [95% CI 0.78-0.95], p-value 3.80E-03), is implicated causally in reducing MS risk. We found no evidence for the causal role of LDL-C and the member of cholesterol biosynthesis pathway on MS risk. The MR results also show that lifelong higher HDL-C (OR 1.14 [95% CI 1.04-1.26], p-value 7.94E-03) increases MS risk but TG was not. Furthermore, we found no evidence for the causal role of lipids and genetically mimicked statins on MS severity. There is no evidence of reverse causation between MS risk and lipids. DISCUSSION: Evidence from this study suggests that RAC2 is a genetic modifier of MS risk. Because RAC2 has been reported to mediate some of the pleiotropic effects of statins, we suggest that statins may reduce MS risk through a cholesterol-independent pathway (that is, RAC2-related mechanism(s)). MR analyses also support a causal effect of HDL-C on MS risk.

The role of body fat in multiple sclerosis susceptibility and severity: A Mendelian randomisation study.

OBJECTIVE: The objective of this study was to explore the potential causal associations of body mass index, height, weight, fat mass, fat percentage and non-fat mass in the whole body, arms, legs and trunk (henceforth, 'anthropometric measures') with multiple sclerosis (MS) risk and severity. We also investigated the potential for reverse causation between anthropometric measures and MS risk. METHODS: We conducted a two-sample univariable, multivariable and bidirectional Mendelian randomisation (MR) analysis. RESULTS: A range of features linked to obesity (body mass index, weight, fat mass and fat percentage) were risk factors for MS development and worsened the disease's severity in MS patients. Interestingly, we were able to demonstrate that height and non-fat mass have no association with MS risk or MS severity. We demonstrated that the association between anthropometric measures and MS is not subject to bias from reverse causation. CONCLUSIONS: Our findings provide evidence from human genetics that a range of features linked to obesity is an important contributor to MS development and MS severity, but height and non-fat mass are not. Importantly, these findings also identify a potentially modifiable factor that may reduce the accumulation of further disability and ameliorate MS severity.

Mendelian Randomisation Finds No Causal Association between Urate and Parkinson's Disease Progression.

BACKGROUND: Parkinson's disease (PD) is a common neurodegenerative movement disorder. Observational studies suggest higher levels of plasma urate may protect against Parkinson's risk and progression; however, causality cannot be established. OBJECTIVES: This study set out to determine whether there is a true causal association between urate levels and PD age at onset (AAO) and progression severity using recently released PD AAO and progression genome-wide association study (GWAS) data. METHODS: A large two-sample Mendelian randomization design was employed, using genetic variants underlying urate levels and the latest GWAS data for PD outcomes. RESULTS: This study found no causal association between urate levels and Parkinson's risk, AAO, or progression severity. CONCLUSIONS: Our results predict increasing urate levels as a therapeutic strategy is unlikely to benefit PD patients. © 2021 International Parkinson and Movement Disorder Society.

Alzheimer's disease: the potential of epigenetic treatments and current clinical candidates.

Alzheimer's disease is a progressive and fatal neurodegenerative disease affecting 50 million people worldwide, characterized by memory loss and neuronal degeneration. Current treatments have limited efficacy and there is no cure. Alzheimer's is likely caused by a combination of factors, providing several potential therapeutic targets. One area of interest is the epigenetic regulation of gene expression within the brain. Epigenetic marks, including DNA methylation and histone modifications, show consistent changes with age and in those with Alzheimer's. Some epigenetic regulation has been linked to disease pathology and progression and are the focus of current research. Epigenetic regulators might make promising therapeutic targets yet challenges need to be overcome to generate an efficacious drug lacking deleterious side effects.