SYNUCLEINOPATHIES
- Genetic and spatial maps of alpha-synucleinopathy in distinct CNS cell types and genetic backgrounds. We have developed novel stem-cell derived glial and neuronal models that rapidly produce the hallmark protein pathologies of neurodegeneration. Unbiased proteome-scale screening methods (including CRISPR-Cas9 genome editing and APEX-based in situ proteome labeling) are used to identify genes that modify neurodegenerative phenotypes in these cells and proteins that interact with alpha-synuclein.
- Cellular pathologies associated with distinct biophysical forms (“strains”) of alpha synuclein in stem cell-derived neurons and glia. Recently, considerable interest has arisen around the spread of alpha-syuclein from cell to cell in a “prionoid” fashion. Distinct synucleinopathies arise from different biophysical forms, or “strains”, of misfolded alpha-synuclein. We are examining this hypothesis in a patient-derived model system. Genetic manipulation and single-cell longitudinal imaging are used to understand and track the consequences of alpha-synuclein aggregation.
- The effects of alpha-synuclein on mRNA processing and translation. A variety of model systems are used, from in vitro systems to yeast to patient-derived neurons and glia to better understand how alpha synuclein’s interactions with mRNA binding proteins reflects its intrinsic biology and pathology.
- Neuroinflammatory signaling and microbiome. Increasingly neuroinflammatory processes are considered to be critical in the progression of neurodegenerative diseases, but the specific ways in which neuroimmune signaling is engaged as a result of protein misfolding is unclear. We are investigating how alpha-synuclein may specifically engage pathologic glial and immune responses when it accumulates or misfolds. We are collecting the microbiome of patients who all have suceptibility to Parkinson’s disease but have very different disease outcomes. In a matched mouse model we are studying how the microbes from these patients may be impact neuroinflammation in the brain to alter disease outcome.
- Functional genomics. We are developing biologically driven tools for genomic analysis and patient stratification. Since the misfolding of alpha-synuclein by definition is the central pathology of synucleinopathies, regardless of the cause, we take our molecular maps as a starting point for understand why specific individual succumb to these diseases (and others escape). This project utilizes genomic sequencing data from individual patients, multi-generation kindreds we follow with dominant alpha-synuclein mutations and larger scale genomic datasets. Our ultimate aim is to develop therapeutics that rationally target biologically defined subsets of patients.
- Gene-environment interactions. In a collaboration with Drs Beate Ritz (UCLA) we are systematically analyzing the effects of pesticides known to be associated with Parkinson’s disease in dopamine neurons engineered in our lab to purity. In this project, in collaboration with the Studer lab at Memorial Sloan Ketteinr, we are also working to generate stem cells from an entire population of PD patients in the same dish so population-level gene-environment interactions of many patients can be analyzed and studied simultaneously. This technology will also enable us in time to perform clinical trials “in the dish.”
CEREBELLAR ATAXIAS
We have generated iPSC from patients who harbor CAG tract (polyglutamine-encoding) expansion mutations that lead to neurodegenerative ataxias, including SCA-1, SCA-2, SCA-3, SCA-7, SCA-8 and DRPLA. Beginning with SCA-3 and DRPLA, we are interested in understanding the biological consequences of misfolding of the encoded proteins and the effects on the multi-protein complexes in which they below.
- Gene therapies. Therapeutically, we are interested in whether genetic correction of these expansions is equivalent to knockdown, a project that has consequences for understanding the potential (and also the potential limitations) of antisense gene therapy for these diseases. We have an active project in which we are testing a gene therapy for DRPLA in stem-cell models matched to patients prior to introducing them in a clinical context. The idea is to better understand on- and off-target effects of ASOs and other gene therapies “in the dish” before clinical trial.
CLINICAL RESEARCH
For clinical trainees and applicants, please look under “Clinical Research Questions and Approaches.”