A5037205059- Parkinson's Disease Mechanisms and Treatments
- Neurological diseases and metabolism
- Cellular transport and secretion
- Alzheimer's disease research and treatments
- Nuclear Receptors and Signaling
- Neurological disorders and treatments
- Lysosomal Storage Disorders Research
- Autophagy in Disease and Therapy
- Plant Gene Expression Analysis
- Ubiquitin and proteasome pathways
- Botulinum Toxin and Related Neurological Disorders
- Adenosine and Purinergic Signaling
- Receptor Mechanisms and Signaling
- Nerve injury and regeneration
- Genetic Neurodegenerative Diseases
- Autism Spectrum Disorder Research
- RNA regulation and disease
- Mitochondrial Function and Pathology
- Endoplasmic Reticulum Stress and Disease
- Amyotrophic Lateral Sclerosis Research
- Neuropeptides and Animal Physiology
- Fungal and yeast genetics research
- Banana Cultivation and Research
- Circadian rhythm and melatonin
- RNA Interference and Gene Delivery
Van Andel Institute
2016-2025
Research Network (United States)
2024-2025
Institute for Neurodegenerative Disorders
2013-2017
École Polytechnique Fédérale de Lausanne
2009-2016
Juntendo University
2009-2011
Tokyo Institute of Psychiatry
2011
National Center of Neurology and Psychiatry
2011
Yokohama City University
2011
Johns Hopkins Medicine
2003-2010
Johns Hopkins University
2003-2010
Phosphatase and tensin homolog (PTEN)-induced putative kinase 1 ( PINK1 ) PARK2/Parkin mutations cause autosomal recessive forms of Parkinson's disease. Upon a loss mitochondrial membrane potential (ΔΨ m in human cells, cytosolic Parkin has been reported to be recruited mitochondria, which is followed by stimulation autophagy. Here, we show that the relocation mitochondria induced collapse ΔΨ relies on expression overexpression WT but not mutated causes translocation even cells with normal ....
Mutations in the leucine-rich repeat kinase 2 gene ( LRRK2 ) cause late-onset Parkinson's disease (PD) with a clinical appearance indistinguishable from idiopathic PD. Initial studies suggest that mutations are most common yet identified determinant of PD susceptibility, transmitted an autosomal-dominant mode inheritance. Herein, we characterize and transcript human brain subclone predominant ORF. Exogenously expressed protein migrates at ≈280 kDa is present largely cytoplasm but also...
Mutations in the leucine-rich repeat kinase 2 gene (LRRK2) cause late-onset Parkinson's disease indistinguishable from idiopathic disease. The mechanisms whereby missense alterations LRRK2 initiate neurodegeneration remain unknown. Here, we demonstrate that seven of 10 suspected familial-linked mutations result increased activity. Functional and disease-associated conserved residues reveal critical link between intrinsic guanosine triphosphatase (GTPase) activity downstream requires GTPase...
The PARK8 gene responsible for late-onset autosomal dominant Parkinson's disease encodes a large novel protein of unknown biological function termed leucine-rich repeat kinase 2 (LRRK2). studies herein explore the localization LRRK2 in mammalian brain.Polyclonal antibodies generated against amino or carboxy termini were used to examine biochemical, subcellular, and immunohistochemical distribution LRRK2.LRRK2 is detected rat brain as an approximate 280kDa by Western blot analysis....
Both homozygous (L166P, M26I, deletion) and heterozygous mutations (D149A, A104T) in the DJ-1 gene have been identified Parkinson's disease (PD) patients. The biochemical function subcellular localization of protein not clarified. To date has largely described studies over-expressing tagged vitro. It is known whether over-expressed identical to that endogenously expressed both vitro vivo. clarify DJ-1, we generated three highly specific antibodies investigated endogenous mouse brain tissues...
Parkinson's disease (PD) is a disorder of movement, cognition, and emotion, it characterized pathologically by neuronal degeneration with Lewy bodies, which are cytoplasmic inclusion bodies containing deposits aggregated proteins. Most PD cases appear to be sporadic, but genetic forms the disease, caused mutations in α-synuclein, parkin, other genes, have helped elucidate pathogenesis. Mutations leucine-rich repeat kinase 2 ( LRRK2 ) cause autosomal-dominant Parkinsonism clinical features...
Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene cause late-onset, autosomal dominant familial Parkinson's disease (PD) and also contribute to idiopathic PD. LRRK2 mutations represent most common of PD with clinical neurochemical features that are largely indistinguishable from disease. Currently, transgenic mice expressing wild-type or disease-causing mutants have failed produce overt neurodegeneration, although abnormalities nigrostriatal dopaminergic neurotransmission been...
Mutations in the parkin gene cause early-onset, autosomal recessive Parkinson's disease. Parkin functions as an E3 ubiquitin ligase to mediate covalent attachment of monomers or linked chains protein substrates. Substrate ubiquitination can target proteins for proteasomal degradation a number non-degradative functions. has been shown preserve mitochondrial integrity experimental systems through regulation fission. Upon damage, translocates mitochondria their selective elimination by...
Misfolded alpha-synuclein (αSyn) is a major constituent of Lewy bodies and neurites, which are pathological hallmarks Parkinson's disease (PD). The contribution αSyn to PD well established, but the detailed mechanism remains obscure. Using model in aggregation primary neurons was seeded by exogenously added, preformed amyloid fibrils (PFF), we found that majority pathogenic (indicated serine 129 phosphorylated αSyn, ps-αSyn) membrane-bound associated with mitochondria. In contrast, only...
The identification of rare monogenic forms Parkinson's disease (PD) has provided tremendous insight into the molecular pathogenesis this disorder. Heritable mutations in α-synuclein, parkin, DJ-1 and PINK1 cause familial PD. In more common sporadic form PD, oxidative stress derangements mitochondrial complex-I function are considered to play a prominent role pathogenesis. However, relationship with other PD-linked genes not been explored. Here, we show that pathogenic mutant specifically but...
The identification of genetic mutations responsible for rare familial forms Parkinson's disease (PD) have provided tremendous insight into the molecular pathogenesis this disorder. Mutations in DJ-1 gene cause autosomal recessive early onset PD two European families. A Dutch kindred displays a large homozygous genomic deletion encompassing exons 1-5 gene, whereas an Italian harbors single L166P missense mutation. M26I mutation was also recently reported Ashkenazi Jewish patient with PD. are...
Mutation in leucine-rich repeat kinase-2 ( LRRK2 ) is the most common cause of late-onset Parkinson's disease (PD). Although cases PD are sporadic, some inherited, including those caused by mutations. Because these mutations may be associated with a toxic gain function, controlling expression decrease its cytotoxicity. Here we show that carboxyl terminus HSP70-interacting protein (CHIP) binds, ubiquitinates, and promotes ubiquitin proteasomal degradation LRRK2. Overexpression CHIP protects...
Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are associated with late-onset, autosomal-dominant, familial Parkinson's disease (PD) and also contribute to sporadic disease. The LRRK2 encodes a large protein multiple domains, including functional Roc GTPase domains. most likely cause through toxic gain-of-function mechanism. expression of human variants cultured primary neurons induces toxicity that is dependent on intact GTP binding or activities. However, mechanism(s)...
Parkinson's disease (PD), a progressive neurodegenerative characterized by bradykinesia, rigidity, and resting tremor, is the most common movement disorder. Although majority of PD cases are sporadic, some inherited, including those caused leucine-rich repeat kinase 2 (LRRK2) mutations. The substitution serine for glycine at position 2019 (G2019S) in domain LRRK2 represents prevalent genetic mutation both familial apparently sporadic PD. Because mutations likely associated with toxic gain...
Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene cause late-onset Parkinson's disease (PD). Emerging evidence suggests a role for LRRK2 endocytic pathway. Here, we show that is released extracellular microvesicles (i.e. exosomes) from cells natively express LRRK2. localizes to collecting duct epithelial kidney actively secrete exosomes into urine. Purified urinary contain protein both dimerized and phosphorylated. We provide quantitative proteomic profile of 1673 proteins find...
Mutations in the ATP13A2 gene (PARK9, OMIM 610513) cause autosomal recessive, juvenile-onset Kufor-Rakeb syndrome and early-onset parkinsonism. is an uncharacterized protein belonging to P5-type ATPase subfamily that predicted regulate membrane transport of cations. The physiological function mammalian brain poorly understood. Here, we demonstrate localized intracellular acidic vesicular compartments cultured neurons. In human brain, pyramidal neurons within cerebral cortex dopaminergic...
Mutations within the leucine-rich repeat kinase 2 (LRRK2) gene account for a significant proportion of autosomal-dominant and some late-onset sporadic Parkinson's disease. Elucidation LRRK2 protein function in health disease provides an opportunity deciphering molecular pathways important neurodegeneration. In mammals, LRRK1 comprise unique family encoding GTPase domain that controls intrinsic activity. The expression profiles murine LRRK proteins have not been fully described insufficiently...
Mutations in the vacuolar protein sorting 35 homolog (VPS35) gene at PARK17 locus, encoding a key component of retromer complex, were recently identified as new cause late-onset, autosomal dominant Parkinson's disease (PD). Here we explore pathogenic consequences PD-associated mutations VPS35 using number model systems. exhibits broad neuronal distribution throughout rodent brain, including within nigrostriatal dopaminergic pathway. In human levels and are similar tissues from control PD...
The G2019S mutation in the leucine-rich repeat kinase 2 (LRRK2) gene is most common genetic cause of Parkinson's disease (PD), accounting for a significant proportion both autosomal dominant familial and sporadic PD cases. Our aim present study to generate mammalian model mutant LRRK2 pathogenesis, which reproduces robust nigral neurodegeneration characteristic PD. We developed adenoviral vectors drive neuron-specific expression full-length wild-type or human nigrostriatal system adult rats....
Mutations in the LRRK2 gene cause autosomal dominant Parkinson's disease. encodes a multi-domain protein containing Ras-of-complex (Roc) GTPase domain, C-terminal of Roc domain and kinase domain. can function as kinase, although interplay between these two enzymatic domains is poorly understood. Although guanine nucleotide binding critically required for activity LRRK2, contribution GTP hydrolysis not known. In general, molecular determinants regulating how contributes to properties remain...