A5037379163- Parkinson's Disease Mechanisms and Treatments
- Lysosomal Storage Disorders Research
- Cellular transport and secretion
- Autophagy in Disease and Therapy
- Receptor Mechanisms and Signaling
- Nerve injury and regeneration
- Neuroscience and Neuropharmacology Research
- Fungal and yeast genetics research
- Genetic Neurodegenerative Diseases
- Ginkgo biloba and Cashew Applications
- Plant Gene Expression Analysis
- Neurotransmitter Receptor Influence on Behavior
- Nuclear Receptors and Signaling
- CRISPR and Genetic Engineering
- Plant biochemistry and biosynthesis
- RNA Interference and Gene Delivery
- Calcium signaling and nucleotide metabolism
- Alzheimer's disease research and treatments
- RNA regulation and disease
- Neurological diseases and metabolism
- Estrogen and related hormone effects
- Neuropeptides and Animal Physiology
- Virus-based gene therapy research
- Pluripotent Stem Cells Research
- Autism Spectrum Disorder Research
Michael J. Fox Foundation
2019-2025
Northwestern University
2022
Columbia University
2017
Columbia University Irving Medical Center
2013
Augusta University
2008-2012
Walker (United States)
2008
Parkinson’s disease (PD) is the most common neurodegenerative movement disorder, and neuroprotective or disease-modifying interventions remain elusive. High-throughput markers aimed at stratifying patients on basis of shared etiology are required to ensure success therapies in clinical trials. Mitochondrial dysfunction plays a prominent role pathogenesis PD. Previously, we found brain region–specific accumulation mitochondrial DNA (mtDNA) damage PD neuronal culture animal models, as well...
Abstract Parkinson´s disease (PD) is a common neurodegenerative movement disorder and leucine-rich repeat kinase 2 (LRRK2) promising therapeutic target for intervention. However, the ability to stratify patients who will benefit from such treatment modalities based on shared etiology critical success of disease-modifying therapies. Ciliary centrosomal alterations are commonly associated with pathogenic LRRK2 activity can be detected in many cell types. We previously found deficits...
Abstract Background LRRK2 mutations are a common cause of dominantly inherited PD. Previous studies showed decreases in urine levels didocohexaenoyl (22:6) bis(monoacylglycerol)phosphate ‐knockout mice and non‐human primates treated with kinase inhibitors. We hypothesized that isoforms will be higher individuals PD‐causing gain‐of‐kinase function mutation, G2019S. The objective this study was to investigate alterations urinary phospholipids as biomarkers Parkinson's disease...
ABSTRACT Background Biallelic mutations in the GBA1 gene encoding glucocerebrosidase cause Gaucher's disease, whereas heterozygous carriers are at risk for Parkinson's disease (PD). Glucosylsphingosine is a clinically meaningful biomarker of but could not be assayed previously carriers. Objective The aim this study was to assess plasma glucosylsphingosine levels N370S with and without PD. Methods Glucosylsphingosine, glucosylceramide, four other lipids were quantified from heterozygotes (n =...
Until recently, about three-quarters of all monogenic Parkinson's disease (PD) studies were performed in European/White ancestry, thereby severely limiting our insights into genotype-phenotype relationships at a global scale.
Abstract Background Leucine‐rich repeat kinase 2 inhibitors are being vigorously pursued as potential therapeutic options; however, there is a critical need for sensitive and quantitative assays of leucine‐rich function target engagement. Objectives Our objective was to compare collection storage protocols peripheral blood mononuclear cells, determine the optimal conditions downstream analyses in PD cohorts. Methods Here, we describe enzyme‐linked immunosorbent assay–based capable detecting...
The role of mitochondria in Parkinson’s disease (PD) has been investigated since the 1980s and is gaining attention with recent advances PD genetics research. Mutations PRKN PTEN-Induced Putative Kinase 1 (PINK1) are well-established causes autosomal recessive early-onset PD. Genetic biochemical studies have revealed that PINK1 Parkin proteins function together same biological pathway to govern mitochondrial quality control. These also implicated regulation innate adaptive immunity other...
We used multiple imaging assays to test the hypothesis that GPR6, a constitutively active Gs-coupled receptor, is present on cell surface. A pHluorin tag at N-terminus of rat GPR6 expressed in human embryonic kidney 293 (HEK293) cells was not accessible protons, chymotrypsin or anti-green fluorescent protein antibody, demonstrating primarily located intracellular compartments. Similar localization pHluorin-tagged found striatal neurons, where endogenous expressed. Confirmation Gs-mediated...
The mechanisms regulating expression of the dopamine transporter are poorly understood. We tested hypothesis that neuronal activity is one non-genetic determinants abundance. Sustained changes in caused by tetrodotoxin and 4-aminopyridine altered uptake abundance its mRNA rat mesencephalic cultures. these two drugs accompanied intracellular calcium concentrations Ca(2+)/calmodulin-dependent protein (CaM) kinase II neurons. Chronic treatment with an L-type channel blocker (nifedipine) or CaM...
SUMMARY The prevalence of Parkinson’s disease (PD) is increasing but the development novel treatment strategies and therapeutics altering course would benefit from specific, sensitive non-invasive biomarkers to detect PD early. Here, we describe a scalable mass spectrometry (MS)-based proteomic workflow for urinary proteome profiling. Our enabled reproducible quantification more than 2,000 proteins in 200 urine samples using minimal volumes two independent patient cohorts. was significantly...
The leucine rich repeat kinase 2 (LRRK2) is the most frequently mutated gene in hereditary Parkinson' disease (PD) and all pathogenic LRRK2 mutations result hyperactivation of its function. Here, we describe an easy robust assay to quantify pathway activity human peripheral blood neutrophils by measuring LRRK2-controlled phosphorylation one physiological substrates, Rab10 at threonine 73. immunoblotting analysis described requires a fully selective phosphospecific antibody that recognizes...
Abstract Mutations enhancing the kinase activity of LRRK2 cause Parkinson’s disease (PD) and therapies that reduce are being tested in clinical trials. Numerous rare variants unknown significance have been reported, but how vast majority impact on function is unknown. Here, we investigate 100 linked to PD, including previously described pathogenic mutations. We identify 23 robustly stimulate activity, within N-terminal non-catalytic regions [ARM (E334K, A419V), ANK(R767H), LRR (R1067Q,...
Since 2005, The Michael J. Fox Foundation for Parkinson's Research (MJFF) has invested significant funding and non-funding effort to accelerate research drug development activity around the Parkinson disease (PD)-associated protein LRRK2. MJFF spearheaded multiple public/private pre-competitive collaborations that have contributed our understanding of LRRK2 function; de-risked potential safety questions therapeutic use kinase inhibitors; generated critical tools, biosamples, data field....
Parkinson's disease (PD) is a chronic, neurodegenerative condition characterized by motor symptoms such as bradykinesia, rigidity, and tremor, alongside multiple nonmotor symptoms.The appearance of linked to progressive dopaminergic neuron loss within the substantia nigra.PD incidence increases sharply with age, suggesting strong association between mechanisms driving biological aging development progression PD.However, role in pathogenesis PD remains understudied.Numerous models PD,...
<title>Abstract</title> LRRK2-related Parkinson’s disease (LRRK2-PD) is the most frequent form of monogenic PD worldwide, with important therapeutic opportunities, exemplified by advancement in LRRK2 kinase inhibition studies/trials. However, many variants, especially those found underrepresented populations, remain classified as variants uncertain significance (VUS). Leveraging on Malaysian, Singaporean, and mainland Chinese datasets (n=4,901), we describe 12 Chinese-ancestry patients...
Abstract Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene have been recognized as genetic risk factors for both familial and sporadic forms of Parkinson’s disease (PD). However, compared to cancer, overall lower mutations contribute cause PD, propelling search protein biomarkers early detection disease. Utilizing 141 urine samples from four groups, healthy individuals (control), with G2019S mutation LRRK2 (non-manifesting carrier/NMC), PD without (idiopathic PD/iPD), (LRRK2 PD), we...
ABSTRACT The phosphorylated form of LRRK2, pS935 has been proposed as a target modulation biomarker for LRRK2 inhibitors. To qualify the therapeutic trials, we assessed levels in Peripheral Blood Mononuclear Cells (PBMCs). Analyses PBMCs from healthy controls, idiopathic Parkinson’s disease (iPD), and G2019S carriers with without PD showed significant reductions normalized to total compared those or iPD. Neither analyte correlated age, gender, severity. Thus, may reflect state marker -driven PD.