A5074368848- Parkinson's Disease Mechanisms and Treatments
- Autophagy in Disease and Therapy
- Trace Elements in Health
- Neuroscience and Neuropharmacology Research
- Ubiquitin and proteasome pathways
- RNA regulation and disease
- Neural dynamics and brain function
- Nuclear Receptors and Signaling
- Heavy Metal Exposure and Toxicity
- Muscle Physiology and Disorders
- Signaling Pathways in Disease
- Sirtuins and Resveratrol in Medicine
- Memory and Neural Mechanisms
- Calcium signaling and nucleotide metabolism
- Cellular transport and secretion
- Alzheimer's disease research and treatments
- Neuroscience and Neural Engineering
- Ion channel regulation and function
- Advanced Memory and Neural Computing
- Venomous Animal Envenomation and Studies
- Toxin Mechanisms and Immunotoxins
- Endoplasmic Reticulum Stress and Disease
- Receptor Mechanisms and Signaling
- Iron Metabolism and Disorders
National University of Singapore
2004-2022
National Neuroscience Institute
2004-2018
It is widely accepted that the familial Parkinson's disease (PD)-linked gene product, parkin, functions as a ubiquitin ligase involved in protein turnover via ubiquitin-proteasome system. Substrates ubiquitinated by parkin are hence thought to be destined for proteasomal degradation. Because we demonstrated previously interacts with and ubiquitinates synphilin-1, initially expected synphilin-1 degradation enhanced presence of parkin. Contrary our expectation, found normally nonclassical,...
Mutations in parkin are currently recognized as the most common cause of familial Parkinsonism. Emerging evidence also suggests that expression variability may confer a risk for development more common, sporadic form Parkinson's disease (PD). Supporting this, we have recently demonstrated solubility human brain becomes altered with age. As apparently functions broad-spectrum neuroprotectant, resulting decrease availability soluble age underlie progressive susceptibility to stress....
Parkinson disease (PD), a prevalent neurodegenerative motor disorder, is characterized by the rather selective loss of dopaminergic neurons and presence α-synuclein-enriched Lewy body inclusions in substantia nigra midbrain. Although etiology PD remains incompletely understood, emerging evidence suggests that dysregulated iron homeostasis may be involved. Notably, nigral are enriched iron, uptake which facilitated divalent metal ion transporter DMT1. To clarify role PD, we generated SH-SY5Y...
Background Mutations in the parkin gene, which encodes a ubiquitin ligase (E3), are major cause of autosomal recessive parkinsonism. Although parkin-mediated ubiquitination was initially linked to protein degradation, accumulating evidence suggests that enzyme is capable catalyzing multiple forms modifications including monoubiquitination, K48- and K63-linked polyubiquitination. In this study, we sought understand how single could exhibit such multifunctional catalytic properties. Methods...
Long-term potentiation (LTP) is the persistent increase in strength of synapses. However, neural networks would become saturated if there only synaptic strenghthening. Synaptic weakening could be facilitated by active processes like long-term depression (LTD). Molecular mechanisms that facilitate synapses and thereby stabilize are also important learning memory. Here we show blockade dopaminergic D4 receptors (D4R) promoted formation late-LTP transformed early-LTP into late-LTP. This effect...
Manganese (Mn(2+)) neurotoxicity from occupational exposure is well documented to result in a Parkinson-like syndrome. Although the understanding of Mn(2+) cytotoxicity still incomplete, both and Fe(2+) can be transported via divalent metal transporter 1 (DMT1), suggesting that competitive uptake might disrupt homeostasis. Here, we found DMT1 overexpression significantly enhanced cytoplasmic accumulation JNK phosphorylation, leading reduction cell viability. robust activation autophagy was...
Elevated iron deposition has been reported in Parkinson's disease (PD). However, the route of uptake leading to high substantia nigra is unresolved. Here, we show a mechanism enhanced Fe 2+ via S-nitrosylation divalent metal transporter 1 (DMT1). While DMT1 could be S-nitrosylated by exogenous nitric oxide donors, human PD brains, endogenously was detected postmortem nigra. Patch-clamp electrophysiological recordings and assays confirmed increased Mn or through DMT1. We identified two major...
Exposure to divalent metals such as iron and manganese is thought increase the risk for Parkinson's disease (PD). Under normal circumstances, cellular uptake regulated by metal transporter 1 (DMT1). Accordingly, alterations in DMT1 levels may underlie abnormal accumulation of ions thereby pathogenesis. Here, we have generated transgenic mice overexpressing under direction a mouse prion promoter demonstrated its robust expression several regions brain. When fed with iron-supplemented diet,...
Disruption of the ubiquitin-proteasome system, which normally identifies and degrades unwanted intracellular proteins, is thought to underlie neurodegeneration. Supporting this, mutations Parkin, a ubiquitin ligase, are associated with autosomal recessive parkinsonism. Remarkably, Parkin can protect neurons against wide spectrum stress, including those that promote proteasome dysfunction. Although mechanism underlying preservation function by hitherto unclear, we have previously proposed...
Abstract Mammalian Target of Rapamycin (mTOR) is a master regulator autophagy and lysosomes, its downstream kinase-dependent pathways have been extensively characterized. Here, we report an unexpected kinase-independent regulation lysosomes by S-nitrosylation at Cys423 position mTOR that resulted in suppression VPS34 PIKfyve-dependent phosphoinositide synthesis. Physiologically, reduced basal lysosomal proteolysis via nitric oxide synthase (NOS)-mediated synthesis NO from arginine precursor,...
Abstract Tone-evoked synaptic excitation and inhibition are highly correlated in many neurons with V-shaped tuning curves the primary auditory cortex of pentobarbital-anesthetized rats. In contrast, there is less correlation between spontaneous visual under same anesthetic conditions. However, it was not known whether resembles having that than tone-evoked inhibition. Here we report whole-cell voltage-clamp measurements The larger excursions both excitatory inhibitory currents appeared to...