Clarissa Waites, PhD

  • Associate Professor of Pathology and Cell Biology and Neuroscience
Profile Headshot


Academic Appointments

  • Associate Professor of Pathology and Cell Biology and Neuroscience

Administrative Titles

  • Associate Vice Chair for Research and Training


  • Female

Credentials & Experience

Education & Training

  • PhD, Neuroscience, University of California , San Francisco
  • BS, Biological Sciences, Stanford University


The overall goal of our research is to understand nervous system function and dysfunction at the cellular and molecular level, focusing on pathways that regulate protein trafficking, degradation, and secretion. Within this broad framework, Waites lab members are currently working on several related but distinct projects, including 1) investigating roles of the ESCRT pathway in neuronal protein degradation and neurodegenerative disease etiology, 2) elucidating the cellular/molecular mechanisms by which chronic stress and glucocorticoids induce brain pathology, and 3) illuminating the mechanisms of extracellular vesicle biogenesis and secretion.

Current Projects

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? 

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 (A?)?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.

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. A?, 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.

Selected Publications

  • Yu Q, Du F, Belli I, Gomes, PA, Sotiropoulos I, Waites CL. Glucocorticoid stress hormones stimulate vesicle-free Tau secretion and spreading in the brain (2023). bioRxiv. Jun 7:2023.06.07.544054. doi: 10.1101/2023.06.07.544054. Preprint.PMID: 37333306. Under review at Cell Death & Disease.
  • Du F, Yu Q, Swerdlow RH, Waites CL. Glucocorticoid-driven mitochondrial damage stimulates Tau pathology (2023). Brain. Apr 18:awad127. doi: 10.1093/brain/awad127. Online ahead of print. PMID: 37070763.
  • Gomes P, Tzouanou F, Skolariki K, Vamvaka-Iakovou A, Noguera-Ortiz C, Tsirtsaki K, Waites CL, Vlamos P, Sousa N, Costa-Silva B, Kapogiannis D, Sotiropoulos I. Extracellular vesicles and Alzheimer’s disease in the novel era of Precision Medicine: implications for disease progression, diagnosis, and treatment (2022). Exp Neurol. 358:114183. doi: 10.1016/j.expneurol.2022.114183. Epub 2022 Aug 8.PMID: 35952764.
  • Gomes PA, Bodo C, Nogueras-Ortiz C,  Samiotaki M, Chen M, Soares-Cunha C, Silva JM, Coimbra B, Stamatakis  G, Santos L, Panayotou G, Tzouanou F, Waites CL, Gatsogiannis C, Sousa N, Kapogiannis D, Costa-Silva B, Sotiropoulos I (2023). A novel isolation method for spontaneously released extracellular vesicles from brain tissue and its implications for stress-driven brain pathology. Cell Commun Signal. 21(1):35. doi: 10.1186/s12964-023-01045-z.PMID: 36782237.
  • Birdsall V, Kirwan K,  Zhu M, Imoto Y, Wilson SM, Watanabe S, Waites CL (2022). Axonal transport of Hrs is activity dependent and facilitates synaptic vesicle protein degradation. Life Sci. Alliance, 5(10):e202000745. doi: 10.26508/lsa.202000745. Print 2022 Oct. PMID: 35636965.
  • Waites C.L., Xu Q, and Bartolini F (2021). The Synaptic Life of Microtubules. Invited review, Curr Opin Neurobiol. April 16;69:113-123. doi: 10.1016/j.conb.2021.03.004.
  • Zhuravleva V, Vaz-Silva J, Zhu M, Gomes P, Silva JM, Sousa N, Sotiropoulos I, Waites CL (2021). Rab35 and glucocorticoids regulate APP and BACE1 trafficking to modulate Ab production. Cell Death Dis. 12(12):1137. doi: 10.1038/s41419-021-04433-w. PMID: 34876559.
  • Monteiro-Fernandes D, Silva JM, Carina Soares-Cunha C, Dalla C, Nikolaos Kokras N, François A, Billiras R, Zhuravleva V, Waites C, Bretin S, Sousa N, Sotiropoulos I (2021). Allosteric modulation of AMPA receptors counteracts Tau-related excitotoxic synaptic signaling and memory deficits in Stress and Aβ-evoked hippocampal pathology. Molecular Psychiatry. 26(10):5899-5911. doi: 10.1038/s41380-020-0794-5. Epub 2020 May 28.PMID: 32467647.
  • Qu X, Kumar A, Blockus H, Waites C, Bartolini F (2019). Activity-dependent nucleation of dynamic microtubules at presynaptic boutons controls neurotransmission. Curr Biol. Dec 16;29(24):4231-4240.e5. doi: 10.1016/j.cub.2019.10.049. 
  • Birdsall V., Martinez J.C., Randolph L., Hengst U., Waites C.L. (2019). Live imaging of ESCRT proteins in microfluidically isolated hippocampal axons. In: Methods Mol Bio. 1998:117-128. doi:10.1007/978-1-4939-9492-2_9.
    Birdsall V., Waites C.L. (2018). Autophagy at the synapse. Neurosci Lett. 697, 24-28. doi: 10.1016/j.neulet.2018.05.033.
  • Zhu M, Cortese G, Waites CL (2018). Parkinson’s disease-linked Parkin mutations impair glutamatergic signaling in hippocampal neurons. BMC Biology. 16(1):100. doi:10.1186/s12915-018-0567-7.
  • Vaz-Silva J, Gomes P, Jin Q, Zhu M, Zhuravleva V, Quintremil S, Meira T, Silva J, Dioli C, Soares-Cunha C, Daskalakis NP, Sousa N, Sotiropoulos I, Waites CL (2018). Endolysosomal degradation of Tau and its role in hippocampal malfunction. EMBO J., 37(20). pii: e99084.doi:10.15252/embj.201899084.
  • Dunn M, Boltaev U, Beskow A, Pampou S, Realubit R, Meira T, Vaz Silva J, Karan C, Jockusch S, Sulzer D, Chang YT, Sames D, Waites CL (2018). Identification of fluorescent small molecule compounds for synaptic labeling by image-based, high-content screening. ACS Chem Neurosci. Dec 18. doi:10.1021/acschemneuro.7b00263.