1. Roles of the ESCRT pathway in protein degradation and neurodegeneration

Degradative pathways are essential for maintaining nervous system health by preventing toxic protein accumulation and aggregation. Our lab has been studying one such pathway, the ESCRT (endosomal sorting complex required for transport), comprising a series of protein complexes (ESCRT-0, -I, -II, -III) that recognize ubiquitinated substrates and package them into multivesicular bodies (MVBs) for delivery to lysosomes. Work in the Waites lab has shown that the ESCRT pathway mediates the degradation of specific synaptic vesicle (SV) proteins in an activity-dependent manner. Based on these findings, we have become very interested in the mechanisms of ESCRT pathway localization, transport, and regulation in neurons, as well as the ESCRT pathway’s role in SV protein turnover and presynaptic function. Moreover, mutations in ESCRT components are associated with frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), and we are interested in how these perturb normal ESCRT trafficking and function to precipitate neurodegeneration. Some of the questions we are addressing include: How are the different ESCRT components transported to synapses, and what types of stimuli catalyze their transport and synaptic recruitment? How are SV proteins targeted and sorted into the ESCRT pathway for degradation? What are the consequences of ESCRT protein mutation/loss-of-function on SV protein turnover, neurotransmitter release, and broader synaptic function? What are the other presynaptic and neuronal substrates of the ESCRT pathway? 

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2. How do chronic stress and glucocorticoids cause brain pathology?

Chronic stress and high levels of glucocorticoids, the major stress hormones, are known risk factors for several neuropsychiatric disorders (i.e. anxiety, depression, PTSD) and neurodegenerative diseases, including Alzheimer’s disease (AD). We are studying the cellular and molecular mechanisms of stress-induced brain pathology, particularly those relevant to AD etiology, using a combination of in vitro and in vivo approaches to illuminate how stress and glucocorticoids contribute to 1) overproduction of toxic amyloid-beta (Ab) peptides, 2) impairment of the endolysosomal pathway and other degradative pathways, 3) mitochondrial dysfunction, 4) Tau pathology and its propagation between brain regions, and 5) neuroinflammation. 

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3. Mechanisms of extracellular vesicle biogenesis and secretion

Extracellular vesicles (EVs) are nano-sized vesicles that contain diverse cargoes (lipids, proteins, nucleic acids), are secreted by all cell types, and mediate cell-to-cell communication. In the brain, EVs have roles in many biological processes including development, homeostasis, synaptic plasticity, and the immune response. EVs are also implicated in the progression of neurodegenerative diseases such as Alzheimer’s disease through their role in spreading pathogenic proteins (i.e. Ab, Tau) throughout the brain. However, little is known about the basic mechanisms of EV biogenesis, secretion, uptake, and transmission between cells, or how these processes are regulated. We are investigating these mechanisms for a population of small EVs called ‘exosomes’, using a combination of biochemical and live imaging approaches in cell culture, ex vivo brain slices, and in vivo mouse models.

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