Tracy Young-Pearse, Ph.D.
The Young-Pearse lab uses molecular approaches to study the functions of genes involved in neurodegenerative and neurodevelopmental diseases.
Tracy Young-Pearse's research group focuses on two main areas.
The identification of novel therapeutic targets for treating Alzheimer’s disease (AD)
Our lab began iPSC modeling of AD with a focus on a single, strong genetic linkage - a fully penetrant missense mutation in the gene APP that causes an early-onset form of the disease. With these lines, we showed that this mutation altered the cleavage profile of APP to affect the types of Aβ secreted. We showed an important link between this altered Aβ, and the levels and phosphorylation state of tau. We used neurons from these lines to test two anti-Aβ immunotherapies and were the first to show that APP mutant neurons responded to these treatments to rescue the tau phenotype.
While informative, these studies modeled one early-onset subtype of AD, and anti-Aβ immunotherapy may not be sufficiently effective in all AD patients. In order to identify and test novel therapeutic targets for late-onset AD, we are interrogating cohorts of aging humans followed longitudinally until death, after which their donate brain tissue is extensively profiled. These cohorts have demonstrated what some clinicians and pathologists suspected, that AD is not a homogeneous disease. With our collaborators, we have developed iPSC lines from over 100 members of these cohorts that span the clinical and neuropathological spectrum of aging. We are using these lines to disentangle the molecular roads leading to risk and resilience to AD.
We complement this human in vitro work with in vivo rodent studies to identify the molecular mechanisms underlying AD. Currently, we are interrogating the heterogeneity of late-onset AD observed in our cohort studies by examining human stem-cell derived neurons, astrocytes, microglia, endothelial cells and pericytes across 100 genetic backgrounds. In addition, we have utilized CRISPR-Cas9 to examine the function of genes associated with AD and related disorders using human iPSC technology. In parallel, we utilize large -omics data sets of human tissue (single nucleus and bulk RNAseq, tandem-mass-tag mass spectrometry, TMT-MS) as well as directed analyses of human tissue using ELISA, western blotting and immunostaining to validate key findings from human iPSC models. We recently found that full length aqueous-soluble INPP5D protein levels are reduced in the Alzheimer’s brain and that reduction in expression of INPP5D in microglia results in inflammasome activation that has consequences on the gene expression profile of neurons. In a separate study, we examined the function of SORL1 in neurons, astrocytes, microglia and endothelial cells. We found that neurons and astrocytes were the most affected by loss of SORL1 (as measured by RNAseq and TMT-MS), and that reduction of SORL1 results in a neuron-specific reduction in APOE and CLU levels. Finally, using a combination of human cellular models, animal models, and analyses of plasma and brain tissue from a large cohort of humans, we showed AD-protective CLU alleles enhance CLU upregulation in response to accumulated neuropathology, thereby dampening inflammatory signaling between microglia and astrocytes. In that study, we showed that CLU upregulation in astrocytes protects neurons from microglia-mediated induction of phospho-tau and synapse loss.
The identification of convergent cell and molecular pathways that lead to autism spectrum disorder and neuropsychiatric disorders
New genetic findings in conjunction with stem cell models of human development provide an unprecedented opportunity to illuminate the cell and molecular bases of mental illness and developmental disorders. A major challenge to iPSC modeling of these disorders is that we are attempting to recapitulate subtle changes in subsets of cells in brain development and maturation. The challenge is compounded by the heterogeneity of both the clinical presentation and the genetic and environmental effectors of these diseases. Our approach is to focus on specific genetic disruptions individually, and then to compare genetic disruptions of similar clinical presentation, to look for points of convergence at the molecular and circuitry level.
Our lab has used patient derived iPSC lines coupled to gene editing to uncover mechanisms underlying bipolar disorder, schizophrenia, autism and Down syndrome. We have identified functional consequences of disruption of genes implicated in these disorders using a combination of human experimental systems and animal experimental systems. First, we identified a biochemical and functional linkage between APP and Disrupted in schizophrenia-1 (DISC1) and demonstrated that DISC1 mediates the effects of APP on migration of neural precursor cells. Further, we have genetically engineered multiple mutations in hiPSCs in the gene DISC1 and compared these engineered cells with iPSCs from patients with DISC1 mutation and showed that DISC disruption results in an elevation of baseline WNT signaling in neural progenitor cells which results in altered proliferation and patterning of developing neural structures. Through these studies we found that POU3F2 is dysregulated downstream of DISC1. POU3F2 is a neural transcription factor that has been implicated in BD through GWAS studies. Our ongoing efforts have utilized CRISPR-Cas9 to introduce null mutations in POU3F2 in human iPSCs. NPCs and neurons generated from the iPSCs show a dysregulation of WNT signaling and alterations in transcriptional networks also affected in brain tissue from those with BD and SCZ. Ongoing studies of POU3F2 conditional knock out mice allowed us to reduce POU3F2 expression either during development or in postmitotic neurons, and effects on neurobiology are now being studied. In addition to neuropsychiatric diseases, we also have studied other neurodevelopmental disorders. Recently we have shown that Trisomy 21 neurons show dysregulated synaptic vesicle release and that normalization of copy number of DYRK1A or APP rescues this defect. Finally, we have found that loss-of-function mutations in SLC9A6 (NHE6), which cause a syndromic form of autism called Christianson syndrome, affect tau proteostasis through dysregulated autophagy.
Biosketch
Tracy Young-Pearse, co-leader of the HSCI Nervous System Diseases Program, is an Associate Professor in the Ann Romney Center for Neurologic Diseases at Brigham and Women’s Hospital and Harvard Medical School in the Department of Neurology. She received her undergraduate degree from Skidmore College in her hometown of Saratoga Springs, NY. She then went on to enter the Biomedical and Biological Sciences (BBS) program at Harvard Medical School, where she received her Ph.D. in Genetics in the lab of Connie Cepko. She then completed a postdoctoral fellowship under the mentorship of Dennis Selkoe before starting her own lab in 2010.