SUMMARY
The research of Rosa Rademakers, Ph.D., within the Department of Neuroscience, is centered around the molecular genetic analyses of neurodegenerative diseases, with a focus on Alzheimer's disease (AD), frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS).
Dr. Rademaker's laboratory seeks to identify novel causal genes, as well as genetic risk factors using family-based genetics and association analyses in well-characterized patient populations. To better understand the function of newly identified genes and mutations, and the mechanism associated with neurodegeneration, her laboratory further employs in vitro molecular approaches.
Her research is funded by the National Institutes of Health, and specifically through the Mayo Clinic Alzheimer's Disease Research Center, the Mayo Clinic Morris K. Udall Center of Excellence in Parkinson's Disease Research and the National Institute of Neurological Disorders and Stroke. Dr. Rademakers also receives grant support from the ALS Therapy Alliance, the Florida Department of Health's Ed and Ethel Moore Alzheimer's Disease Research Program, and the Consortium for Frontotemporal Dementia Research.
Focus areas
- Identification and study of genetic regulators of progranulin (GRN). Dr. Rademakers' work in families with a history of frontotemporal dementia led to the discovery of mutations in GRN as a major cause of early-onset dementia. Since then, her laboratory played an important role in the identification and characterization of mutations in GRN, in the identification and study of regulators of GRN protein expression and in the development of a GRN ELISA as a simple blood test to identify mutations in symptomatic and presymptomatic mutation carriers.
- C9orf72 and other novel genes implicated in frontotemporal dementia and amyotrophic lateral sclerosis. Dr. Rademakers' laboratory recently identified a noncoding repeat expansion in the C9orf72 gene as the most common cause of ALS and FTD. In an attempt to explain the clinical variability associated with this common mutation, her laboratory has already identified several genetic disease modifiers, including additional mutations in progranulin (GRN) and microtubule-associated protein tau (MAPT), but also intermediate repeats in ataxin 2 (ATXN2) and variants in transmembrane protein 106B (TMEM106B). Whole-genome sequencing studies aimed at the identification of additional modifiers are currently ongoing.
- Identification of novel Alzheimer's disease (AD) genes and disease-associated pathways. In an effort to improve understanding of Alzheimer's disease and impact patient care, the laboratory recently initiated a large, early-onset AD study to identify novel genes and cellular pathways associated with AD. As part of this effort, the laboratory created the Florida Presenile Alzheimer's Disease Subjects (FPADS) registry to systematically recruit patients across Florida with early-onset AD. Exome sequencing will be used to identify novel candidate AD genes in inherited (familial) forms of the disease and in patients with sporadic AD.
- Genetic analyses of familial tauopathies. Dr. Rademakers' laboratory is also involved in the identification of novel genes and genetic risk factors driving the abnormal accumulation of tau protein (tau pathology) in patients diagnosed with progressive supranuclear palsy or corticobasal generation at autopsy. The goal is to identify novel genes for these parkinsonian syndromes using whole-genome sequencing in families. More information is available from the Morris K. Udall Center of Excellence for Parkinson's Disease Research.
Significance to patient care
Overall, the neurogenetic studies performed in Dr. Rademakers' laboratory are expected to improve molecular diagnostic accuracy and counseling, including the development of early disease biomarkers. Identification of novel disease genes may further reveal novel targets that can be exploited for therapeutic actions aimed at preventing or delaying the development of AD, FTD, ALS and related disorders.