A5002571663- Parkinson's Disease Mechanisms and Treatments
- Alzheimer's disease research and treatments
- Nuclear Receptors and Signaling
- RNA regulation and disease
- Cellular transport and secretion
- Neurological diseases and metabolism
- Mitochondrial Function and Pathology
- RNA Research and Splicing
- Genetic Neurodegenerative Diseases
- Cholinesterase and Neurodegenerative Diseases
- Nerve injury and regeneration
- Genetics, Aging, and Longevity in Model Organisms
- Neurological disorders and treatments
- Neurobiology and Insect Physiology Research
- interferon and immune responses
- Autophagy in Disease and Therapy
- Endoplasmic Reticulum Stress and Disease
- Lysosomal Storage Disorders Research
- Neuroinflammation and Neurodegeneration Mechanisms
- Dementia and Cognitive Impairment Research
- Neuroscience and Neuropharmacology Research
- Cancer-related cognitive impairment studies
- Autism Spectrum Disorder Research
- Ubiquitin and proteasome pathways
- Prion Diseases and Protein Misfolding
Harvard University
2016-2025
Brigham and Women's Hospital
2016-2025
Center for Pain and the Brain
2022-2025
Research Network (United States)
2022-2024
Chestnut Hill College
2024
Massachusetts General Hospital
2007-2023
Harvard University Press
2005-2009
MaineGeneral Medical Center
2009
Scripps Research Institute
2007
Purdue University West Lafayette
2007
Parkinson's disease (PD) is a common neurodegenerative disorder characterized by loss of dopaminergic neurons in the substantia nigra. Several lines evidence strongly implicate mitochondrial dysfunction as major causative factor PD, although molecular mechanisms responsible for are poorly understood. Recently, loss-of-function mutations parkin gene, which encodes ubiquitin-protein ligase, were found to underlie familial form PD known autosomal recessive juvenile parkinsonism (AR-JP). To gain...
The sirtuins are members of the histone deacetylase family proteins that participate in a variety cellular functions and play role aging. We identified potent inhibitor sirtuin 2 (SIRT2) found inhibition SIRT2 rescued alpha-synuclein toxicity modified inclusion morphology model Parkinson's disease. Genetic via small interfering RNA similarly toxicity. Furthermore, inhibitors protected against dopaminergic cell death both vitro Drosophila results suggest link between neurodegeneration
The microtubule-binding protein tau has been implicated in the pathogenesis of Alzheimer's disease and related disorders. However, mechanisms underlying tau-mediated neurotoxicity remain unclear. We created a genetic model tau-related neurodegenerative by expressing wild-type mutant forms human fruit fly Drosophila melanogaster . Transgenic flies showed key features disorders: adult onset, progressive neurodegeneration, early death, enhanced toxicity tau, accumulation abnormal relative...
α-synuclein is a neuronal protein implicated genetically in Parkinson's disease. localizes to the nucleus and presynaptic nerve terminals. Here we show that mediates neurotoxicity nucleus. Targeting of promotes toxicity, whereas cytoplasmic sequestration protective both cell culture transgenic Drosophila . Toxicity can be rescued by administration histone deacetylase inhibitors flies. binds directly histones, reduces level acetylated H3 cultured cells inhibits acetylation acetyltransferase...
Abstract Background Elevated SNCA gene expression and intracellular accumulation of the encoded α-synuclein (aSyn) protein are associated with development Parkinson disease (PD). To date, few enzymes have been examined for their ability to degrade aSyn. Here, we explore effects CTSD expression, which encodes lysosomal protease cathepsin D (CathD), on aSyn processing. Results Over-expression human cDNA in dopaminergic MES23.5 cell cultures induced marked proteolysis exogenously expressed...
### Introduction The past decade has witnessed a burst of speculation and data about how astrocyte dysfunction contributes to the phenotypes well known neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, amyotrophic lateral sclerosis, other types
Alpha-synuclein (αS) is a conformationally plastic protein that reversibly binds to cellular membranes. It aggregates and genetically linked Parkinson's disease (PD). Here, we show αS directly modulates processing bodies (P-bodies), membraneless organelles function in mRNA turnover storage. The N terminus of αS, but not other synucleins, dictates mutually exclusive binding either membranes or P-bodies the cytosol. associates with multiple decapping proteins close proximity on Edc4 scaffold....
Markers of oxidative damage have been detected in brain tissue from patients with Alzheimer disease (AD) and other neurodegenerative disorders. These findings implicate injury the process, but whether stress is a cause or consequence neurotoxicity remains unclear. We used Drosophila model human tauopathies to investigate role neurodegeneration. Genetic pharmacological manipulation antioxidant defense mechanisms significantly modified neurodegeneration our model, suggesting that plays causal...
Mutations in the synaptic protein α-synuclein cause rare genetic forms of Parkinson's disease. α-Synuclein is thought to play a critical role more common sporadic cases disease as well because aggregates hallmark intraneuronal inclusions disorder, Lewy bodies. To test aggregation pathogenesis disease, we expressed form with deletion amino acids 71–82 that unable aggregate vitro transgenic Drosophila model disorder. We found no evidence large or oligomeric species these animals and loss...
Mutations in genes required for associative learning and memory Drosophila exist, but isolation of the has been difficult because most are defined by a single, chemically induced allele. Here, simplified genetic screen was used to identify candidate involved memory. Second site suppressors dunce ( dnc ) female sterility phenotype were isolated with use transposon mutagenesis. One suppressor mutation that recovered mapped amnesiac amn gene. Cloning locus revealed encodes previously...
Several neurodegenerative disorders contain tau-immunoreactive neuronal and glial inclusions throughout the cerebral cortex brainstem. Although these diseases have been considered distinct clinicopathological entities, recent recognition of many neuropathological clinical parallels has raised question overlap between disorders. In addition, histopathological similarities sometimes complicate diagnosis. To address issues, we examined morphology differential distribution pathologic lesions in...
Abstract In Alzheimer's disease and related disorders, the microtubule-associated protein Tau is abnormally hyperphosphorylated aggregated into neurofibrillary tangles. Mutations in tau gene cause familial frontotemporal dementia. To investigate molecular mechanisms responsible for Tau-induced neurodegeneration, we conducted a genetic modifier screen Drosophila model of tauopathy. Kinases phosphatases comprised major class modifiers recovered, several candidate kinases were similarly shown...