PrP turnover in vivo and the time to effect of prion disease therapeutics.

PrP lowering is effective against prion disease in animal models and is being tested clinically. Therapies in the current pipeline lower PrP production, leaving pre-existing PrP to be cleared according to its own half-life. We hypothesized that PrP's half-life may be a rate-limiting factor for the time to effect of PrP-lowering drugs, and one reason why late treatment of prion-infected mice is not as effective as early treatment.

Alpha-synuclein null mutation exacerbates the phenotype of a model of Menkes disease in female mice.

Genetic modifier screens provide a useful tool, in diverse organisms from to and mice, for recovering new genes of interest that may reduce or enhance a phenotype of interest. This study reports a modifier screen, based on N-ethyl-N-nitrosourea (ENU) mutagenesis and outcrossing, designed to increase understanding of the normal function of murine α-synuclein (). Human was the first gene linked to familial Parkinson's disease.

Therapeutic Trial of anle138b in Mouse Models of Genetic Prion Disease.

Phenotypic screening has yielded small-molecule inhibitors of prion replication that are effective against certain prion strains but not others. Here, we sought to test the small molecule anle138b in multiple mouse models of prion disease. In mice inoculated with the RML strain of prions, anle138b doubled survival and durably suppressed astrogliosis measured by live-animal bioluminescence imaging.

Parkinson's Disease: Overview of Transcription Factor Regulation, Genetics, and Cellular and Animal Models.

Parkinson's disease (PD) is one of the most common neurodegenerative disorders, affecting nearly 7-10 million people worldwide. Over the last decade, there has been considerable progress in our understanding of the genetic basis of PD, in the development of stem cell-based and animal models of PD, and in management of some clinical features. However, there remains little ability to change the trajectory of PD and limited knowledge of the underlying etiology of PD.

Regional variability and genotypic and pharmacodynamic effects on PrP concentration in the CNS.

Prion protein (PrP) concentration controls the kinetics of prion replication and is a genetically and pharmacologically validated therapeutic target for prion disease. In order to evaluate PrP concentration as a pharmacodynamic biomarker and assess its contribution to known prion disease risk factors, we developed and validated a plate-based immunoassay reactive for PrP across 6 species of interest and applicable to brain and cerebrospinal fluid (CSF). PrP concentration varied dramatically across different brain regions in mice, cynomolgus macaques, and humans.