A5061967495- Parkinson's Disease Mechanisms and Treatments
- Cellular transport and secretion
- Lysosomal Storage Disorders Research
- Neurological disorders and treatments
- Alzheimer's disease research and treatments
- Nuclear Receptors and Signaling
- Genetic Neurodegenerative Diseases
- Botulinum Toxin and Related Neurological Disorders
- Autism Spectrum Disorder Research
- Autophagy in Disease and Therapy
- Neuroinflammation and Neurodegeneration Mechanisms
- Lipid metabolism and biosynthesis
- Advanced Electron Microscopy Techniques and Applications
- Adipose Tissue and Metabolism
- Carbohydrate Chemistry and Synthesis
- Retinal Diseases and Treatments
- Neurological diseases and metabolism
- Neuroscience and Neuropharmacology Research
- Calcium signaling and nucleotide metabolism
- Lipid Membrane Structure and Behavior
- Metabolism, Diabetes, and Cancer
- Enzyme Structure and Function
- Nerve injury and regeneration
- Retinal Imaging and Analysis
- Advanced X-ray Imaging Techniques
Brigham and Women's Hospital
2021-2025
Harvard University
2021-2025
Amsterdam University Medical Centers
2018-2024
Vrije Universiteit Amsterdam
2014-2024
Amsterdam Neuroscience
2014-2023
Amsterdam UMC Location Vrije Universiteit Amsterdam
2014-2018
Center for Neurosciences
2017
Next to α-synuclein deposition, microglial activation is a prominent pathological feature in the substantia nigra (SN) of Parkinson's disease (PD) patients. Little known, however, about different phenotypes microglia and how they change during progression, SN or another brain region, like hippocampus (HC), which implicated dementia depression, important non-motor symptoms PD. We studied HC established PD patients (Braak stage 4–6), matched controls 0) incidental Lewy Body (iLBD) cases 1–3)...
Abstract Various post-translationally modified (PTM) proteoforms of alpha-synuclein (aSyn)—including C-terminally truncated (CTT) and Serine 129 phosphorylated (Ser129-p) aSyn—accumulate in Lewy bodies (LBs) different regions the Parkinson’s disease (PD) brain. Insight into distribution these within LBs subcellular compartments may aid understanding orchestration pathology PD. We applied epitope-specific antibodies against CTT Ser129-p aSyn domains immunohistochemical multiple labelings on...
Abstract In Parkinson’s disease and other synucleinopathies, the elevation of α-synuclein phosphorylated at Serine129 (pS129) is a widely cited marker pathology. However, physiological role for pS129 has remained undefined. Here we use multiple approaches to show first time that functions as regulator neuronal activity. Neuronal activity triggers sustained increase in cultured neurons (200% within 4 h). accord, brain elevated environmentally enriched mice exhibiting enhanced long-term...
Mutations in the GBA gene, encoding lysosomal hydrolase glucocerebrosidase (GCase), are most common known genetic risk factor for Parkinson's disease (PD) and dementia with Lewy bodies (DLB). The present study aims to gain more insight into changes activity different brain regions of sporadic PD DLB patients, screened variants. Enzymatic activities GCase, β-hexosaminidase, cathepsin D were measured frontal cortex, putamen, substantia nigra (SN) a cohort patients advanced as well age-matched...
Abstract Mutations in the α-Synuclein (αS) gene promote αS monomer aggregation that causes neurodegeneration familial Parkinson’s disease (fPD). However, most mouse models expressing single-mutant transgenes develop neuronal aggregates very slowly, and few have dopaminergic cell loss, both key characteristics of PD. To accelerate neurotoxic aggregation, we previously generated fPD E46K mutant mice with rationally designed triple mutations based on α-helical repeat motif structure (fPD E46K→3...
Lewy bodies (LBs) are pathological hallmarks of Parkinson’s disease and dementia with bodies, characterized by the accumulation α-synuclein (αSyn) protein in brain. While LBs were first described a century ago, their formation morphogenesis mechanisms remain incompletely understood. Here, we present historical overview LB definitions highlight importance semantic clarity precise when describing brain inclusions. Recent breakthroughs imaging revealed shared features within subsets enrichment...
Significance The mechanisms responsible for brain α-synuclein (αS) dyshomeostasis, caused by Gaucher’s GBA1 mutations that increase Parkinson’s disease (PD) risk, are largely unknown. We previously showed abrogating physiological αS tetramers a familial PD-E46K–amplified 3K mutation produces PD-like syndrome in mice and treatment with stearoyl-CoA desaturase inhibitors increased portion of the tetramers, benefitting motor phenotypes. Here, we show that—similar to previous findings...
Impaired lipid metabolism is a risk factor for Parkinson's disease (PD) and dementia with Lewy bodies (DLB) can shift the physiological α-synuclein (αS) tetramer-monomer (T:M) ratio toward aggregation prone monomers. A resultant increase in phospho-serine 129+ αS monomers associating excess mono- polyunsaturated fatty acids contributes to aggregation. We previously reported that decreasing release of monounsaturated (MUFAs) by reducing or inhibiting hormone sensitive lipase (LIPE) reversed...
Summary Parkinson’s disease, the most common age-related movement disorder, is a progressive neurodegenerative disease with unclear etiology. Key neuropathological hallmarks are Lewy bodies and neurites, which neuronal inclusions that immunopositive for protein α-synuclein. In-depth ultrastructural analysis of this pathology crucial to understanding pathogenesis progression disease. Using correlative light electron microscopy/tomography on brain tissue from five donors, we identified...
Abstract Transcription factor EB (TFEB) is a master regulator of genes involved in the maintenance autophagic and lysosomal homeostasis, processes which have been implicated pathogenesis GBA -related sporadic Parkinson’s disease (PD), dementia with Lewy bodies (DLB). TFEB activation results its translocation from cytosol to nucleus. Here, we investigated subcellular localization relation intracellular alpha-synuclein (aSyn) accumulation post-mortem human brain individuals either incidental...
Based on immunostainings and biochemical analyses, certain post-translationally modified alpha-synuclein (aSyn) variants, including C-terminally truncated (CTT) Serine-129 phosphorylated (pSer129) aSyn, are proposed to be involved in the pathogenesis of synucleinopathies such as Parkinson's disease with (PDD) without dementia (PD), Lewy bodies (DLB), multiple system atrophy (MSA). However, quantitative information about aSyn proteoforms human brain physiological different pathological...
Parkinson’s disease (PD) is characterized by conversion of soluble α-synuclein (αS) into intraneuronal aggregates and degeneration neurons neuronal processes. Indications that women with early-stage PD display milder neurodegenerative features suggest female sex partially protects against αS pathology. We previously reported estradiol improved homeostasis PD-like phenotypes in E46K-amplified (3K) mice. Here, we aimed to further dissect mechanisms drive this dimorphism early disease. observed...
Next to α-synuclein deposition, microglial activation is a prominent pathological feature in the substantia nigra (SN) of Parkinson's disease (PD) patients. Little known, however, about different phenotypes microglia and how they change during progression, SN or another brain region, like hippocampus (HC), which implicated dementia depression, important non-motor symptoms PD. We studied HC established PD patients (Braak stage 4–6), matched controls 0) incidental Lewy Body (iLBD) cases 1–3)...
Abstract Post-translational modifications of alpha-synuclein (aSyn), particularly phosphorylation at Serine 129 (Ser129-p) and truncation its C-terminus (CTT), have been implicated in Parkinson’s disease (PD) pathology. To gain more insight the relevance Ser129-p CTT aSyn under physiological pathological conditions, we investigated their subcellular distribution patterns normal aged PD brains using highly-selective antibodies combination with 3D multicolor STED microscopy. We show that...
Gaining insight to pathologically relevant processes in continuous volumes of unstained brain tissue is important for a better understanding neurological diseases. Many pathological neurodegenerative disorders affect myelinated axons, which are critical part the neuronal circuitry. Cryo ptychographic X-ray computed tomography multi-keV energy range an emerging technology providing phase contrast at high sensitivity, allowing label-free and non-destructive three dimensional imaging large...