Efficacy of Fumaric Acid Esters in the R6/2 and YAC128 Models of Huntington's Disease

Huntington's disease (HD) is an autosomal dominantly inherited progressive neurodegenerative disease. The exact sequel of events finally resulting in neurodegeneration is only partially understood and there is no established protective treatment so far. Some lines of evidence speak for the contribution of oxidative stress to neuronal tissue damage. The fumaric acid ester dimethylfumarate (DMF) is a new disease modifying therapy currently in phase III studies for relapsing-remitting multiple sclerosis. DMF potentially exerts neuroprotective effects via induction of the transcription factor “nuclear factor E2-related factor 2” (Nrf2) and detoxification pathways. Thus, we investigated here the therapeutic efficacy of DMF in R6/2 and YAC128 HD transgenic mice which mimic many aspects of HD and are characterized by an enhanced generation of free radicals in neurons. Treatment with DMF significantly prevented weight loss in R6/2 mice between postnatal days 80–90. At the same time, DMF treatment led to an attenuated motor impairment as measured by the clasping score. Average survival in the DMF group was 100.5 days vs. 94.0 days in the placebo group. In the histological analysis on day 80, DMF treatment resulted in a significant preservation of morphologically intact neurons in the striatum as well as in the motor cortex. DMF treatment resulted in an increased Nrf2 immunoreactivity in neuronal subpopulations, but not in astrocytes. These beneficial effects were corroborated in YAC128 mice which, after one year of DMF treatment, also displayed reduced dyskinesia as well as a preservation of neurons. In conclusion, DMF may exert beneficial effects in mouse models of HD. Given its excellent side effect profile, further studies with DMF as new therapeutic approach in HD and other neurodegenerative diseases are warranted

Polygenic scores for handedness and their association with asymmetries in brain structure

Handedness is the most widely investigated motor preference in humans. The genetics of handedness and especially the link between genetic variation, brain structure, and right-left preference have not been investigated in detail. Recently, several well-powered genome-wide association studies (GWAS) on handedness have been published, significantly advancing the understanding of the genetic determinants of left and right-handedness. In the present study, we estimated polygenic scores (PGS) of handedness-based on the GWAS by de Kovel and Francks (Sci Rep 9: 5986, 2019) in an independent validation cohort (n = 296). PGS reflect the sum effect of trait-associated alleles across many genetic loci. For the first time, we could show that these GWAS-based PGS are significantly associated with individual handedness lateralization quotients in an independent validation cohort. Additionally, we investigated whether handedness-derived polygenic scores are associated with asymmetries in gray matter macrostructure across the whole brain determined using magnetic resonance imaging. None of these associations reached significance after correction for multiple comparisons. Our results implicate that PGS obtained from large-scale handedness GWAS are significantly associated with individual handedness in smaller validation samples with more detailed phenotypic assessment. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00429-021-02335-3