Green neurons

Research Interests

We are interested in understanding the basic cellular mechanisms of neurodegeneration in Alzheimer’s disease, frontotemporal dementia, chronic traumatic encephalopathy and other neurodegenerative disorders. The ultimate goal is to translate relevant findings into therapies for our patients. Novel approaches are needed given the large number of clinical trial failures in the neurodegenerative disease field. Current studies in the lab include:

  • RNA processing dysfunction in AD - Recent studies identified aggregates of small nuclear ribonucleoproteins (snRNPs) in AD in addition to dysfunctional RNA splicing. Current studies utilizing traditional biochemical and cell culture techniques in addition to more advance proteomic and RNA sequencing are ongoing to understanding the role of dysfunctional RNA splicing in AD. These studies are also aimed at better understanding the role of RNA processing dysfunction in chronic traumatic encephalopathy (CTE) and the overlap with AD. A new project to investigate how aggregating RNA processing factors impact that aggregation of tau has also just started. RNA processing factor aggregates

  • Proteomic sequencing of AD, FTD and CTE - We will often rely on proteomic sequencing of postmortem human brain to identify proteins that may be involved the process of neurodegeneration. Thanks to funding from the Department of Defense, we have a project sequencing increasing stages of CTE for comparison with other tauopathies so as to understand the molecular overlaps and to identify potential modifiers of tau. Further validation of promising targets will be preformed in cell culture based assays including stem cell derived cell lineages.

  • Utilizing human induced pluripotent stem cells (IPSc) to understand how microtubule protein tau (MAPT) genetic mutations cause frontotemporal dementia - Mutations in the MAPT gene can lead to frontotemporal dementia however it remains unclear as to how these mutations ultimate lead to neurodegeneration. The goal of this project is to utilize differentiated neurons developed from IPS cells and other cellular and biochemical techniques to identify dysfunctional cellular pathways that may contribute to the disease process. IPS cells are generate in the lab from fibroblasts that are collected from research volunteers who harbor MAPT genetic mutations. We are especially interested in MAPT mutations P301L and R406W. Genomic editing techniques (CRISPR/Cas9) are being explored to generate isogenic lines for comparative study. We are also interested in ‘aging’ differentiated cell lines so as to better recapitulate neurodegenerative changes. The ultimate goal is to identify human relevant targets that can be translated into therapies for our patients. IPS to neuron figure

  • Understanding extracellular neuronal network activity in neurodegeneration - Human cognition is based on the electrical activity generated by billions of neurons divided into distinct functional networks. Neurodegenerative diseases like Alzheimer’s disease and frontotemporal dementia lead to dysfunctional network activity that manifests as impaired cognition. Understanding this process may be helpful in generating new therapies. Therefore one aspect of the lab is devoted to evaluating various neurodegenerative disease models (including primary rodent and human IPSc derived neurons) in dissociated neuronal networks on microelectrode arrays. Our recording system is the Maestro by Axion Biosystems. IPS neuron on MEA

  • Related changes across various neurodegenerative disorders There are likely common mechanisms that are important for many of the primary neurodegenerative disorders. As a result, we have collected fibroblast samples for generating IPS cells from many different research subjects for comparative analysis in the above mentioned assays. Diseases include Alzheimer’s disease, frontotemporal dementia, ALS, Parkinson’s disease, and autism.