The Neuroscience of Psychedelics
In collaboration with the Center for the Neuroscience of Psychedelics at MGH, the Haggarty Lab has now begun new projects investigating the ethnopharmacology of psychoactive plant and fungal-derived natural products. Our laboratory's interest in studying these compounds arises from their remarkable ability to serve as modulators of neuroplasticity, which may hold therapeutic potential in a wide range of neurological and psychiatric disorders. We are interested in uncovering the molecular, cellular, and network level underpinnings of these molecules while learning from and respecting the Indigenous Peoples and traditions that have utilized these compounds for centuries.
Our laboratory is actively working towards mechanistic studies of various psychoactive molecules and towards the synthesis of psychoactives with novel pharmacokinetic and pharmacodynamic profiles. We are also beginning to investigate the endogenous synthesis of psychoactive molecules.
Targeting disease-associated proteins in neurological and neuropsychiatric disorders
Our laboratory is interested in characterizing and targeting phenotypes incurred by disease-associated proteins in neurological (e..g, Tau, PGRN, TDP-43) and neuropsychiatric disorders (TCF4, CIC, TSC, FMR1). Select examples of active targets in the lab are included below:
Neurodegeneration refers to the loss of neuronal function and viability of cells in the human brain. A shared feature among neurodegenerative disorders is the accumulation of aberrant and deleterious protein inclusions in the most affected brain regions. In the case of frontotemporal dementia (FTD) spectrum disorders, one of such proteins is tau, an abundant microtubule-associated protein involved in diverse aspects of neuronal structure and physiology. Tauopathies, including FTD, are still without effective treatment, with few tau-specific therapeutics entering clinical trials.
Our goal is to investigate the step-by-step progression and development of pathophysiology, and specifically identify the early molecular and biochemical changes in iPSC-derived, patient-specific neurons, that potentially represent the stages when therapeutics would be more effective before overt neuronal death. This system is also a powerful platform for testing small molecules, introducing the human context early in the drug discovery pipeline. To identify drugs with disease-modifying therapeutic potential, we work with different series of small molecules that reduce tau burden and toxicity in these patient-derived neuronal cell models. Some of these experimental drugs include tau-targeted protein degraders (PROTACs, AUTACs), enhancers of the autophagy-lysosomal machinery, and modifiers of tau spreading and seeding.
Some of the most significant genetic risk factors for FTD outside of MAPT (Tau) are mutations in GRN, which encodes progranulin (PGRN). Near ubiquitously, these mutations cause haploinsufficiency of PGRN. Progranulin deficiency causes broad lysosomal dysfunction characterized by inclusion-filled lysosomes and increased expression of lysosomal proteins such as cathepsin D and LAMP1. Moreover, recent literature has characterized PGRN as a modulator of microglial activity, as PGRN deficient microglia are pathological in their impaired ability to phagocytose extracellular debris as well as in their increased expression of complement genes.
Our laboratory aims to further characterize the phenotypes incurred by PGRN haploinsufficiency in various iPSC-derived cell types, and to identify small-molecules that can restore haploinsufficient PGRN expression to wild-type levels. Current efforts towards this goal include generating and utilizing a microglia-based PGRN luciferase reporter line for high-throughput screening efforts, as well as characterization (both cell-based and in murine models) and mechanistic studies into novel classes of epigenetic-targeting small-molecules previously identified in the laboratory.
Dysregulation of WNT/β-catenin signaling has been implicated in the etiology and pathophysiology of multiple neuropsychiatric and neurodegenerative disorders. For instance, loss-of-function mutations in CTNNB1, the gene that encodes β-catenin, have been identified in several individuals with intellectual disability, while disruptions to the psychiatric risk gene ankyrin 3 (ANK3) have been shown to interfere with microtubule dynamics through activation of signaling by GSK and the collapsing response mediator protein 2 (CRMP2). WNT signaling has also been shown to promote mRNA and protein expression of transcription factor 4 (TCF4), mutations in which are implicated in Pitt-Hopkins syndrome, schizophrenia, and autism spectrum disorders.
Our laboratory is interested in discovering and characterizing novel activators of the WNT/β-catenin signaling pathway. We have previously designed and validated a sensitive, high-throughput screening-compatible WNT/β-catenin reporter system in human neural progenitor cells derived from iPSCs. Utilizing this screening system, we were able to conduct a screen of over 300,000 compounds. After extensive follow-up and functional validation, we identified multiple novel chemotypes of WNT/β-catenin enhancers in neural progenitor cells which we are now working to mechanistically characterize and evaluate in murine models.
Investigating epigenetic mechanisms and signaling pathways with a role in neuroplasticity
The human brain is capable of remarkable feats of experience-dependent plasticity that enable it to consistently adapt to a changing environment, to learn, and to form stable memories that can guide future behavior. Growing evidence suggests that these mechanisms of neuroplasticity are disrupted in the case of brain disorders and upon the natural process of aging. To better understand these mechanisms and to provide novel therapeutics, our laboratory is developing and applying innovative strategies and technologies for the systematic identification and targeting of the underlying molecular, cellular, and circuit-level mechanisms that regulate neuroplasticity in the central nervous system (CNS). Through probing the mechanisms of neuroplasticity that are critical for health and disease with novel experimental therapeutics, we expect that our studies, in conjunction with emerging evidence from human genetics, will improve our understanding of neuropsychiatric and neurodegenerative disorders and through translational efforts will lead to the development of targeted therapeutics for their prevention and treatment.
Our work has contributed to the recognition of the critical role of epigenetic mechanisms in brain health and disease, which present a whole host of novel therapeutic strategies based upon altering aberrant states of gene expression and chromatin structure. We have also developed novel screening approaches using patient-derived stem cell models that enable the investigation of neuroplasticity and neuropharmacology using human neurons--a feat not previously achievable due to the difficulty of accessing living human neurons that now opens many new avenues for small-molecule discovery. We are now testing our hypotheses both in pre-clinical animal models of memory and mood disorders and in on-going experimental therapeutic trials in patients with our colleagues in the MGH Department of Psychiatry and MIT Picower Institute of Learning & Memory.