Sonnet S. Davis
A5042836509- Alzheimer's disease research and treatments
- Neuroinflammation and Neurodegeneration Mechanisms
- Endoplasmic Reticulum Stress and Disease
- Lysosomal Storage Disorders Research
- Parkinson's Disease Mechanisms and Treatments
- Inflammation biomarkers and pathways
- RNA regulation and disease
- Amyotrophic Lateral Sclerosis Research
- Cellular transport and secretion
- Genetics, Aging, and Longevity in Model Organisms
- Tryptophan and brain disorders
- Neurogenetic and Muscular Disorders Research
- Prion Diseases and Protein Misfolding
- Advanced Glycation End Products research
- Vitamin D Research Studies
- Telomeres, Telomerase, and Senescence
- Metabolomics and Mass Spectrometry Studies
- Immune cells in cancer
- Genomics, phytochemicals, and oxidative stress
- Apelin-related biomedical research
- Circadian rhythm and melatonin
- Neurological Disease Mechanisms and Treatments
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Cholesterol and Lipid Metabolism
- Sirtuins and Resveratrol in Medicine
Denali Therapeutics (United States)
2019-2025
Kaiser Permanente South San Francisco Medical Center
2023
Buck Institute for Research on Aging
2015-2021
Harvard University
2020
Massachusetts General Hospital
2020
Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic risk factors for Parkinson's disease (PD). Increased LRRK2 activity is thought to impair lysosomal function and may contribute pathogenesis of PD. Thus, inhibition a potential disease-modifying therapeutic strategy DNL201 an investigational, first-in-class, CNS-penetrant, selective, ATP-competitive, small-molecule inhibitor. In preclinical models, inhibited as evidenced by reduced phosphorylation both at serine-935...
An enzyme transport vehicle enables brain delivery of lysosomal enzymes across the blood-brain barrier in mice.
Abstract Loss-of-function variants of TREM2 are associated with increased risk Alzheimer’s disease (AD), suggesting that activation this innate immune receptor may be a useful therapeutic strategy. Here we describe high-affinity human TREM2-activating antibody engineered monovalent transferrin (TfR) binding site, termed transport vehicle (ATV), to facilitate blood–brain barrier transcytosis. Upon peripheral delivery in mice, ATV:TREM2 showed improved brain biodistribution and enhanced...
Genetic mutations underlying familial Alzheimer's disease (AD) were identified decades ago, but the field is still in search of transformative therapies for patients. While mouse models based on overexpression mutated transgenes have yielded key insights mechanisms disease, those are subject to artifacts, including random genetic integration transgene, ectopic expression and non-physiological protein levels. The engineering novel using knock-in approaches addresses some limitations. With...
Accumulation of senescent cells is associated with the progression pulmonary fibrosis, but mechanisms accounting for this linkage are not well understood. To explore issue, we investigated whether a class biologically active profibrotic lipids, leukotrienes (LT), part senescence-associated secretory phenotype. The analysis conditioned medium (CM), lipid extracts, and gene expression LT biosynthesis enzymes revealed that secreted LT, regardless origin or modality senescence induction....
While apolipoprotein E (APOE) is the strongest genetic modifier for late-onset Alzheimer's disease (LOAD), molecular mechanisms underlying isoform-dependent risk and relevance of ApoE-associated lipids remain elusive. Here, we report that impaired low-density lipoprotein (LDL) receptor (LDLR) binding lipidated ApoE2 (lipApoE2) avoids LDLR recycling defects observed with lipApoE3/E4 decreases uptake cholesteryl esters (CEs), which are linked to neurodegeneration. In human neurons, addition...
Vitamin D has multiple roles, including the regulation of bone and calcium homeostasis. Deficiency 25-hydroxyvitamin D, major circulating form vitamin is associated with an increased risk age-related chronic diseases, Alzheimer's disease, Parkinson's cognitive impairment, cancer. In this study, we utilized Caenorhabditis elegans to examine mechanism by which influences aging. We found that vitamin-D3-induced lifespan extension requires stress response pathway genes skn-1, ire-1, xbp-1. D3...
<h3>Objective</h3> To identify markers of resistance to developing Parkinson disease (PD) among <i>LRRK2</i> mutation carriers (<i>LRRK2</i>+), we carried out metabolomic profiling in individuals with PD and unaffected controls (UC), without the mutation. <h3>Methods</h3> Plasma from 368 patients UC LRRK2 Cohort Consortium (LCC), comprising 118 <i>LRRK2</i>+/PD+, 115 <i>LRRK2</i>+/UC, 70 <i>LRRK2</i>−/PD+, 65 <i>LRRK2−</i>/UC, CSF available 68 them, were analyzed by liquid chromatography...
Abstract The Alzheimer’s disease (AD) human genetic landscape indicates microglia are an important cell type in the brain that modifies risk. A common loss-of-functon(LOF) coding variant paired immunoglobulin-like 2 receptor alpha (PILRA) is associated with reduced risk of AD, however mechanisms underlying this protective effect poorly defined. Here we identify biological functions PILRA, immunoreceptor tyrosine-based inhibitory motif (ITIM)-containing receptor, iPSC-derived and chimeric...
Abstract Background Frontotemporal dementia (FTD) is the most common cause of early-onset with 10-20% cases caused by mutations in one three genes: GRN , C9orf72 or MAPT . To effectively develop therapeutics for FTD, identification and characterization biomarkers to understand disease pathogenesis evaluate impact specific therapeutic strategies on target biology as well underlying pathology are essential. Moreover, tracking longitudinal changes these throughout progression crucial discern...
Progranulin (PGRN) haploinsufficiency is a major risk factor for frontotemporal lobar degeneration with TAR DNA-binding protein 43 (TDP-43) pathology (FTLD- GRN ). Multiple therapeutic strategies are in clinical development to restore PGRN the CNS, including gene therapy. However, limitation of current therapy approaches aimed alleviate FTLD-associated pathologies may be their inefficient brain exposure and biodistribution. We therefore developed an adeno-associated virus (AAV) targeting...
Abstract Triggering receptor expressed on myeloid cells 2 (TREM2) is a central regulator of microglial activity and sequence variants are major risk factors for late onset Alzheimer’s disease (LOAD). To better understand the molecular functional changes associated with TREM2 signalling, we generated reporter mouse model observed gradual upregulation expression increasing plaque proximity. Isolated microglia were sorted based their transcriptomic profiles acquired in both wildtype APP...
<title>Abstract</title> The Alzheimer’s disease (AD) genetic landscape identified microglia as a key disease-modifying cell type. A known AD protective variant in paired immunoglobulin-like type 2 receptor alpha (PILRA), shown to reduce risk APOE4 carriers, is enriched cohort of healthy centenarians; however, mechanisms underlying effects are undefined. Here we identify biological functions PILRA, an ITIM-domain containing receptor, human iPSC-derived (iMG) and chimeric mice....
Microglia are implicated in modifying neurodegenerative disease risk the central nervous system (CNS). GPR34 is a microglia-enriched G-protein coupled receptor that detects cytotoxic lipids upregulated Alzheimers Disease (AD). Since dysregulated lipid metabolism occurs disease, we hypothesized could act with other sensors, such as TREM2, to regulate microglial function. Here, report knockout (KO) rescues cholesterol TREM2 KO iPSC-derived microglia (iMG) and alone promotes fatty acid...
Abstract Various retinal degenerative diseases including dry and neovascular age-related macular degeneration (AMD), retinitis pigmentosa, diabetic retinopathy are associated with the of pigmented epithelial (RPE) layer retina. This consequently results in death rod cone photoreceptors that they support, structurally functionally leading to legal or complete blindness. Therefore, developing therapeutic strategies preserve cellular homeostasis RPE would be a favorable asset clinic. The aryl...
Mucopolysaccharidosis type II is a lysosomal storage disorder caused by deficiency of iduronate-2-sulfatase (IDS) and characterized the accumulation primary substrate, glycosaminoglycans (GAGs). Understanding central nervous system (CNS) pathophysiology in neuronopathic MPS (nMPS II) has been hindered lack CNS biomarkers. Characterization fluid biomarkers largely focused on evaluating GAGs cerebrospinal (CSF) periphery; however, GAG levels alone do not accurately reflect broad cellular...