A5022616909- Parkinson's Disease Mechanisms and Treatments
- Autophagy in Disease and Therapy
- Mitochondrial Function and Pathology
- Nuclear Receptors and Signaling
- Cellular transport and secretion
- Neurological diseases and metabolism
- Endoplasmic Reticulum Stress and Disease
- Lysosomal Storage Disorders Research
- Ubiquitin and proteasome pathways
- Genetic Neurodegenerative Diseases
- Nerve injury and regeneration
- Alzheimer's disease research and treatments
- Neuroscience and Neuropharmacology Research
- Metabolism and Genetic Disorders
- Cell death mechanisms and regulation
- Genetics and Neurodevelopmental Disorders
- RNA regulation and disease
- Genetics, Aging, and Longevity in Model Organisms
- Amyotrophic Lateral Sclerosis Research
- Neurological disorders and treatments
- Reproductive Biology and Fertility
- Neurobiology and Insect Physiology Research
- Animal Genetics and Reproduction
- Histone Deacetylase Inhibitors Research
- Reproductive Physiology in Livestock
Juntendo University
2015-2024
Tohoku University
2002-2010
RIKEN
2008
RIKEN Center for Brain Science
2000-2008
Stanford University
2005-2007
VA Palo Alto Health Care System
2006-2007
Geriatric Research Education and Clinical Center
2005-2007
Fujita Health University
2005
Osaka University
2005
Cornell University
2005
Mutations in Pink1, a gene encoding Ser/Thr kinase with mitochondrial-targeting signal, are associated Parkinson's disease (PD), the most common movement disorder characterized by selective loss of dopaminergic neurons. The mechanism which Pink1 leads to neurodegeneration is not understood. Here we show that inhibition Drosophila (dPink1) function results energy depletion, shortened lifespan, and degeneration select indirect flight muscles muscle pathology was preceded mitochondrial...
Autosomal recessive juvenile parkinsonism (AR-JP) is caused by mutations in the parkin gene. Parkin protein characterized a ubiquitin-like domain at its NH(2)-terminus and two RING finger motifs an IBR (in between fingers) COOH terminus (RING-IBR-RING). Here, we show that RING-type E3 ubiquitin-protein ligase which binds to E2 ubiquitin-conjugating enzymes, including UbcH7 UbcH8, through RING-IBR-RING motif. Moreover, found unfolded stress induces up-regulation of both mRNA level Parkin....
Parkinson's disease genes PINK1 and parkin encode kinase ubiquitin ligase, respectively. The gene products Parkin are implicated in mitochondrial autophagy, or mitophagy. Upon the loss of membrane potential (ΔΨm), cytosolic is recruited to mitochondria by through an uncharacterised mechanism – initial step triggering sequential events This study reports that Ser65 ubiquitin-like domain (Ubl) phosphorylated a PINK1-dependent manner upon depolarisation ΔΨm. introduction mutations at suggests...
Mutations in Pten-induced kinase 1 (PINK1) are linked to early-onset familial Parkinson's disease (FPD). PINK1 has previously been implicated mitochondrial fission/fusion dynamics, quality control, and electron transport chain function. However, it is not clear how these processes interconnected whether they sufficient explain all aspects of pathogenesis. Here we show that also controls motility. In Drosophila, downregulation dMiro or other components the machinery rescued dPINK1 mutant...
Parkinson's disease (PD) is the most common movement disorder characterized by dopaminergic dysfunction and degeneration. The cause of PD cases unknown, although postmortem studies have implicated involvement oxidative stress. identification familial PD-associated genes offers opportunity to study mechanisms pathogenesis in model organisms. Here, we show that DJ-1A, a Drosophila homologue gene DJ-1, plays an essential role stress response neuronal maintenance. Inhibition DJ-1A function...
Abstract The carboxyl terminus of heat‐shock cognate (Hsc)70‐interacting protein (CHIP) is a ubiquitin E3 ligase that can collaborate with molecular chaperones to facilitate folding and prevent aggregation. Previous studies showed that, together (Hsp)70, CHIP regulate tau ubiquitination degradation in cell culture system. Ubiquitinated one component neurofibrillary tangles (NFTs), which are major histopathological feature Alzheimer's disease (AD). However, the precise sequence events leading...
Mutations in the LRRK2 gene are most common genetic cause of familial Parkinson's disease (PD). However, its physiological and pathological functions unknown. Therefore, we generated several independent Drosophila lines carrying WT or mutant human (mutations kinase, COR LRR domains, resp.). Ectopic expression dopaminergic neurons caused their significant loss accompanied by complex age-dependent changes locomotor activity. Overall, ubiquitous increased lifespan fertility flies. these flies...
The kinase PINK1 and the E3 ubiquitin (Ub) ligase Parkin participate in mitochondrial quality control. phosphorylation of Ser65 Parkin's ubiquitin-like (UBl) domain by stimulates activation translocation to damaged mitochondria, which induces mitophagy generating polyUb chain. However, is insufficient for translocation. Here we report that chain also phosphorylated PINK1, on mitochondria tethers at mitochondria. expression Tom70MTS-4xUb SE, mimics phospho-Ser65 chains activated activity its...
Abstract Mutations in CHCHD2 have been identified some Parkinson’s disease (PD) cases. To understand the physiological and pathological roles of CHCHD2, we manipulated expression Drosophila mammalian cells. The loss causes abnormal matrix structures impaired oxygen respiration mitochondria, leading to oxidative stress, dopaminergic neuron motor dysfunction with age. These PD-associated phenotypes are rescued by overexpression translation inhibitor 4E-BP introduction human but not its...
Mutations of the retromer component Vps35 and endosomal kinase LRRK2 are linked to autosomal dominant forms familial Parkinson's disease (PD). However, physiological pathological roles in neuronal functions poorly understood. Here, we demonstrated that loss Drosophila (dVps35) affects synaptic vesicle recycling, dopaminergic release sleep behavior associated with activity, which is rescued by expression wild-type dVps35 but not PD-associated mutant D647N. dLRRK together Rab5 Rab11 also...
Abstract About two-thirds of the vital genes in Drosophila genome are involved eye development, making fly an excellent genetic system to study cellular function and neurodevelopment/degeneration, complex diseases such as cancer diabetes. We developed a novel computational method, implemented Flynotyper software (http://flynotyper.sourceforge.net), quantitatively assess morphological defects resulting from alterations affecting basic developmental processes. utilizes series image processing...
Significance The mechanisms of α-synuclein aggregation and subsequent Lewy body formation are a key pathogenesis Parkinson’s disease (PD). PARK14 -linked PD, which is caused by mutations the iPLA2-VIA/PLA2G6 gene, exhibits marked pathology. iPLA2-VIA , belongs to phospholipase A 2 family, another causative gene neurodegeneration with brain iron accumulation (NBIA). Here, we demonstrate that loss results in acyl-chain shortening phospholipids, affects ER homeostasis neurotransmission promotes...
Abstract We examined the distribution of Pael‐R, a newly identified substrate for Parkin, in Parkinson's disease (PD) and multiple system atrophy (MSA). α‐synuclein, ubiquitin accumulated Lewy bodies (LBs) neurites. Pael‐R was localized core LBs. Parkin α‐synuclein halo, neuronal cell bodies, processes. These findings potentially suggest involvement LB formation, protection role Pael‐R‐mediated neurotoxicity PD. The absence glial cytoplasmic inclusions (GCIs) MSA implies distinct pathway...
Selective loss of dopaminergic neurons is the final common pathway in Parkinson's disease. Expression Parkin associated endothelin-receptor like receptor (Pael-R) mouse brain was achieved by injecting adenoviral vectors carrying a modified neuron-specific promoter and Cre recombinase into striatum. Upregulation Pael-R substantia nigra pars compacta mice retrograde infection induced endoplasmic reticulum (ER) stress leads to death neurons. The role ER neuronal vulnerability highlighted their...
Missense mutations in leucine-rich repeat kinase 2 (LRRK2)/Dardarin gene, the product of which encodes a with multiple domains, are known to cause autosomal dominant late onset Parkinson's disease (PD). In current study, we report that gene LRRK2 directly phosphorylates forkhead box transcription factor FoxO1 and enhances its transcriptional activity. This pathway was found be conserved Drosophila, as Drosophila homolog (dLRRK) enhanced neuronal toxicity FoxO. Importantly, FoxO mutants were...