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Parkinson Disease: HELP
Articles by Eng King Tan
Based on 139 articles published since 2010
(Why 139 articles?)
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Between 2010 and 2020, E. K. Tan wrote the following 139 articles about Parkinson Disease.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4 · 5 · 6
1 Editorial Stem Cell Replacement Therapies in Parkinson's Disease. 2019

Zeng, Li / Chan, Ling Ling / Lim, Erle Ch / Tan, Eng King. ·Neural Stem Cell Research Laboratory, National Neuroscience Institute, Singapore. ·Ann Acad Med Singapore · Pubmed #31131382.

ABSTRACT: -- No abstract --

2 Editorial Linking statins and lipids in Parkinson's disease. 2017

Ng, Adeline S L / Tan, Eng-King. ·Department of Neurology, National Neuroscience Institute, Tan Tock Seng Hospital, Singapore. · Department of Neurology, National Neuroscience Institute, Singapore General Hospital, Singapore. · Duke-NUS Medical School, Singapore. ·Mov Disord · Pubmed #28556203.

ABSTRACT: -- No abstract --

3 Editorial Familial Parkinson's disease/parkinsonism. 2015

Tomiyama, Hiroyuki / Lesage, Suzanne / Tan, Eng-King / Jeon, Beom S. ·Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan. · Sorbonne Universités, UPMC Université Paris 6 UMRS 1127, Inserm U 1127, CNRS UMR 7225, Institut du Cerveau et de la Moelle Épinière (ICM), Paris, France. · Department of Neurology, Singapore General Hospital and Neuroscience & Behavioral Disorders Program, Duke-NUS Graduate Medical School, National Neuroscience Institute, Singapore. · Department of Neurology, Seoul National University Hospital, Seoul, Republic of Korea. ·Biomed Res Int · Pubmed #25961036.

ABSTRACT: -- No abstract --

4 Editorial Holding on to statins in Parkinson disease. 2013

Tan, Eng-King / Tan, Louis C S. · ·Neurology · Pubmed #23884043.

ABSTRACT: -- No abstract --

5 Editorial Optimizing treatment for Parkinson's disease. 2012

Schapira, A H V / Tan, E K. · ·Eur J Neurol · Pubmed #23157243.

ABSTRACT: -- No abstract --

6 Editorial LRRK2 as a therapeutic target in Parkinson's disease. 2011

Tan, E K / Schapira, A H. · ·Eur J Neurol · Pubmed #21199179.

ABSTRACT: -- No abstract --

7 Editorial New LRRK2 variants identified in Parkinson's disease. 2011

Tan, E K / Schapira, A H. · ·Eur J Neurol · Pubmed #20629720.

ABSTRACT: -- No abstract --

8 Review Historical Perspective: Models of Parkinson's Disease. 2020

Chia, Shyh Jenn / Tan, Eng-King / Chao, Yin-Xia. ·National Neuroscience Institute, Singapore 308433, Singapore. · Department of Neurology, Singapore General Hospital, Singapore 169856, Singapore. · Duke-NUS Medical School, Singapore 169857, Singapore. ·Int J Mol Sci · Pubmed #32252301.

ABSTRACT: Parkinson's disease (PD) is the most common movement disorder with motor and nonmotor signs. The current therapeutic regimen for PD is mainly symptomatic as the etio-pathophysiology has not been fully elucidated. A variety of animal models has been generated to study different aspects of the disease for understanding the pathogenesis and therapeutic development. The disease model can be generated through neurotoxin-based or genetic-based approaches in a wide range of animals such as non-human primates (NHP), rodents, zebrafish,

9 Review Role of MicroRNAs in Parkinson's Disease. 2019

Goh, Suh Yee / Chao, Yin Xia / Dheen, Shaikali Thameem / Tan, Eng-King / Tay, Samuel Sam-Wah. ·Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, 4 Medical Drive, Singapore 117594, Singapore. · National Neuroscience Institute, 11 Jalan Tan Tock Seng, Singapore 308433, Singapore. · Department of Neurology, Singapore General Hospital, Outram Road, Singapore 169608, Singapore. · Medical Education, Research and Evaluation (MERE) department, Duke-NUS Medical School, 8 College Rd, Singapore 169857, Singapore. · Neuroscience and Behavioral Disorders (NBD) department, Duke-NUS Medical School, 8 College Rd, Singapore 169857, Singapore. ·Int J Mol Sci · Pubmed #31718095.

ABSTRACT: Parkinson's disease (PD) is a disabling neurodegenerative disease that manifests with resting tremor, bradykinesia, rigidity and postural instability. Since the discovery of microRNAs (miRNAs) in 1993, miRNAs have been shown to be important biological molecules involved in diverse processes to maintain normal cellular functions. Over the past decade, many studies have reported dysregulation of miRNA expressions in PD. Here, we identified 15 miRNAs from 34 reported screening studies that demonstrated dysregulation in the brain and/or neuronal models, cerebrospinal fluid (CSF) and blood. Specific miRNAs-of-interest that have been implicated in PD pathogenesis include miR-30, miR-29, let-7, miR-485 and miR-26. However, there are several challenges and limitations in drawing definitive conclusions due to the small sample size in clinical studies, varied laboratory techniques and methodologies and their incomplete penetrance of the blood-brain barrier. Developing an optimal delivery system and unravelling druggable targets of miRNAs in both experimental and human models and clinical validation of the results may pave way for novel therapeutics in PD.

10 Review Molecular targets for modulating the protein translation vital to proteostasis and neuron degeneration in Parkinson's disease. 2019

Zhou, Zhi Dong / Selvaratnam, Thevapriya / Lee, Ji Chao Tristan / Chao, Yin Xia / Tan, Eng-King. ·1Department of Research, National Neuroscience Institute, 11 Jalan Tan Tock Seng, Singapore, 308433 Singapore. · 0000 0004 0636 696X · grid.276809.2 · 3Signature Research Program in Neuroscience and Behavioural Disorders, Duke-NUS Medical School Singapore, 8 College Road, Singapore, Singapore. · 0000 0004 0385 0924 · grid.428397.3 · 2Department of Neurology, Singapore General Hospital, Outram Road, Singapore, 169608 Singapore. · 0000 0000 9486 5048 · grid.163555.1 ·Transl Neurodegener · Pubmed #30740222.

ABSTRACT: Parkinson's disease (PD) is the most common neurodegenerative movement disorder, which is characterized by the progressive loss of dopaminergic neurons in the Substantia Nigra pars compacta concomitant with Lewy body formation in affected brain areas. The detailed pathogenic mechanisms underlying the selective loss of dopaminergic neurons in PD are unclear, and no drugs or treatments have been developed to alleviate progressive dopaminergic neuron degeneration in PD. However, the formation of α-synuclein-positive protein aggregates in Lewy body has been identified as a common pathological feature of PD, possibly stemming from the consequence of protein misfolding and dysfunctional proteostasis. Proteostasis is the mechanism for maintaining protein homeostasis via modulation of protein translation, enhancement of chaperone capacity and the prompt clearance of misfolded protein by the ubiquitin proteasome system and autophagy. Deregulated protein translation and impaired capacities of chaperone or protein degradation can disturb proteostasis processes, leading to pathological protein aggregation and neurodegeneration in PD. In recent years, multiple molecular targets in the modulation of protein translation vital to proteostasis and dopaminergic neuron degeneration have been identified. The potential pathophysiological and therapeutic significance of these molecular targets to neurodegeneration in PD is highlighted.

11 Review Amyloid-β and Parkinson's disease. 2019

Lim, Ee Wei / Aarsland, Dag / Ffytche, Dominic / Taddei, Raquel Natalia / van Wamelen, Daniel J / Wan, Yi-Min / Tan, Eng King / Ray Chaudhuri, Kallol / Anonymous151136. ·Parkinson Foundation International Centre of Excellence at King's College Hospital, Denmark Hill, London, SE5 9RS, UK. lim.ee.wei@singhealth.com.sg. · Department of Neurology, National Neuroscience Institute (Singapore General Hospital Campus), 20 College Road, Singapore, 169856, Singapore. lim.ee.wei@singhealth.com.sg. · Duke-National University of Singapore Graduate Medical School, Singapore, 169857, Singapore. lim.ee.wei@singhealth.com.sg. · Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience at King's College London, De Crespigny Park, London, SE5 8AF, UK. · Parkinson Foundation International Centre of Excellence at King's College Hospital, Denmark Hill, London, SE5 9RS, UK. · Department of Neurology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Centre, Reinier Postlaan 4, Postbus 9101, 6500HB, Nijmegen, The Netherlands. · Department of Psychiatry, Ng Teng Fong General Hospital, 1 Jurong East Street 21, Singapore, 609606, Singapore. · Department of Neurology, National Neuroscience Institute (Singapore General Hospital Campus), 20 College Road, Singapore, 169856, Singapore. · Duke-National University of Singapore Graduate Medical School, Singapore, 169857, Singapore. ·J Neurol · Pubmed #30377818.

ABSTRACT: Parkinson's disease (PD) is the second commonest neurodegenerative disorder in the world with a rising prevalence. The pathophysiology is multifactorial but aggregation of misfolded α-synuclein is considered to be a key underpinning mechanism. Amyloid-β (Aβ) and tau deposition are also comorbid associations and especially Aβ deposition is associated with cognitive decline in PD. Some existing evidence suggests that low cerebrospinal fluid (CSF) Aβ

12 Review Pathophysiological mechanisms linking F-box only protein 7 (FBXO7) and Parkinson's disease (PD). 2018

Zhou, Zhi Dong / Lee, Ji Chao Tristan / Tan, Eng King. ·Department of Research, National Neuroscience Institute, 11 Jalan Tan Tock Seng, 308433, Singapore; Signature Research Program in Neuroscience and Behavioural Disorders, Duke-NUS Medical School, 8 College Road, 169857, Singapore. Electronic address: Zhidong_zhou@nni.com.sg. · Department of Research, National Neuroscience Institute, 11 Jalan Tan Tock Seng, 308433, Singapore. Electronic address: tristan.lee.j.c@singhealth.com.sg. · Department of Research, National Neuroscience Institute, 11 Jalan Tan Tock Seng, 308433, Singapore; Department of Neurology, Singapore General Hospital, Outram Road, 169608, Singapore; Signature Research Program in Neuroscience and Behavioural Disorders, Duke-NUS Medical School, 8 College Road, 169857, Singapore. Electronic address: Tan.eng.king@sgh.com.sg. ·Mutat Res · Pubmed #30454685.

ABSTRACT: Mutations of F-box only protein 7 (FBXO7) gene are associated with a severe form of autosomal recessive juvenile Parkinson's disease (PD) (PARK15) with clinical features of Parkinsonian-Pyramidal syndrome (PPS). FBXO7 is an adaptor protein in SCF

13 Review Mild cognitive impairment in Parkinson's disease: a distinct clinical entity? 2017

Wen, Ming-Ching / Chan, Ling Ling / Tan, Louis C S / Tan, Eng King. ·Department of Research, National Neuroscience Institute, Singapore, Singapore. · 0000 0004 0636 696X · grid.276809.2 · Department of Neurology, National Neuroscience Institute, 11 Jalan Tan Tock Seng, Singapore, 308433 Singapore. · Department of Diagnostic Radiology, Singapore General Hospital, Singapore, Singapore. · 0000 0000 9486 5048 · grid.163555.1 · Duke-NUS Medical School, Singapore, Singapore. · 0000 0004 0385 0924 · grid.428397.3 ·Transl Neurodegener · Pubmed #28919975.

ABSTRACT: BACKGROUND: Mild cognitive impairment in Parkinson's disease (PD-MCI) is a common clinical condition. Understanding its pathology and clinical features is important for early intervention before the onset of dementia. In the past, variable definitions and differences in neuropsychological batteries generated divergent results of the affected cognitive patterns. MAIN BODY: The introduction of PD-MCI criteria by the Movement Disorders Society (MDS) Task Force provides a more uniform system for defining and measuring PD-MCI and may improve the validity of future research. PD-MCI is likely to be heterogeneous since it can coexist with Alzheimer's disease and/ or Lewy body pathologies in PD. Pathogeneses of neuropsychiatric disturbances, such as depression, anxiety and apathy, are associated with PD with or without MCI. In addition, cognitive reserve formed by patients' unique life experiences may influence the outward cognitive performance despite the presence of the aforementioned pathogeneses and hence alter the diagnosis of MCI. CONCLUSION: The overlap of cognitive impairment across different neurodegenerative diseases suggests that PD-MCI is likely to result from a mixture of complex pathophysiologies, rather than being a distinct pathologic entity. Differentiating MCI from other organic symptoms in PD would facilitate novel therapeutic strategies.

14 Review Genes and Nonmotor Symptoms in Parkinson's Disease. 2017

Lim, Ee-Wei / Tan, Eng-King. ·National Neuroscience Institute, Duke NUS Medical School, Singapore, Singapore. · National Neuroscience Institute, Duke NUS Medical School, Singapore, Singapore. Electronic address: tan.eng.king@singhealth.com.sg. ·Int Rev Neurobiol · Pubmed #28802918.

ABSTRACT: Published data on genetic risk factors of nonmotor symptoms (NMS) are relatively lacking since the first mutation responsible for Parkinson's disease (PD) being reported in 1996. This chapter provides a concise summary of genetic links to common individual NMS such as cognitive impairment, depression, psychosis, olfactory dysfunction, pain, and sleep disorders. Although some genetic variants such as apolipoprotein E and glucocerebrosidase demonstrate consistent links with certain NMS, it is difficult to draw definitive conclusions. A concerted effort involving standardized protocol in multiple centers and multiethnic groups will be useful to further investigate the association. With the help of high-throughput genomic techniques, more causative genes and novel genes will be discovered in the future and this will contribute further to the understanding of genetic susceptibility of NMS in PD.

15 Review Mood and neural correlates of excessive daytime sleepiness in Parkinson's disease. 2017

Wen, M-C / Chan, L L / Tan, L C S / Tan, E K. ·Department of Research, National Neuroscience Institute, Singapore, Singapore. · Department of Neurology, National Neuroscience Institute, Singapore, Singapore. · Department of Diagnostic Radiology, Singapore General Hospital, Singapore, Singapore. · Duke-National University of Singapore Graduate Medical School, Singapore, Singapore. ·Acta Neurol Scand · Pubmed #28670700.

ABSTRACT: For patients with Parkinson's disease (PD), excessive daytime sleepiness (PD-EDS) is a debilitating non-motor symptom and may be affected by mood symptoms, especially depression and anxiety. Few neuroimaging works have attempted to identify the neural features of PD-EDS, but various findings were reported. The purpose of this study was to systematically review the literature on mood and neuroimaging correlates of PD-EDS. A MEDLINE, PubMed, EMBASE, and PsycInfo search for peer-reviewed original research articles on depression, anxiety, and neuroimaging in PD-EDS identified 26 studies on depression, nine on anxiety, and eight on neuroimaging. Half of the studies reported greater depression in PD-EDS-positive patients compared with PD-EDS-negative patients. There was a significantly positive correlation between depression and PD-EDS. Limited studies on anxiety in PD-EDS suggested a weak correlation between anxiety and EDS. For depression and anxiety, the effect sizes were medium when EDS was subjectively measured, but became small when EDS was objective measured. Current neuroimaging studies generally suggested diminished neural structural and functional features (eg, brain volume, white matter integrity as indicated by fractional anisotropy, and cerebral metabolism) in patients with PD-EDS. Future studies should apply objective and subjective measures of mood symptoms and EDS and improve the neuroimaging methodology via using multimodal techniques and whole-brain analysis to provide new clues on the mood and neural correlates of PD-EDS.

16 Review Targeting LRRK2 in Parkinson's disease: an update on recent developments. 2017

Chan, Sharon L / Tan, Eng-King. ·a Department of Neurology , National Neuroscience institute, Duke NUS Medical School , Singapore. ·Expert Opin Ther Targets · Pubmed #28443359.

ABSTRACT: INTRODUCTION: LRRK2 research has progressed significantly in recent years with more reports of LRRK2 interactors and the development of more specific and sophisticated LRRK2 kinase inhibitors. Identification of bone fide LRRK2 substrates will provide new therapeutic targets in LRRK2-linked Parkinson's disease (PD). Areas covered: This review aims to put current LRRK2 research into perspective. Beginning with recent LRRK2 mammalian models employed for in vivo validation of LRRK2 substrates, followed by updates on reported LRRK2 interactors and their inferred mechanisms. Finally an overview of commonly used LRRK2 kinase inhibitors will be depicted. Expert opinion: Identification of LRRK2 non-kinase functions suggests the possibility of alternative LRRK2 drug target sites and these should be further explored. Studies on the effects of LRRK2 kinase inhibition on its non-kinase function and its self-regulatory role will provide further insights on its pathophysiologic mechanisms. Development of robust measurements of LRRK2 inhibitor efficacy will be required. These would include identification of specific imaging ligands or direct biochemical assays that can accurately capture its intrinsic activity. Testing of new therapeutic drug targets in both LRRK2 carriers and non LRRK2-linked patients will be important since their phenotype is similar.

17 Review Depression, anxiety, and apathy in Parkinson's disease: insights from neuroimaging studies. 2016

Wen, M-C / Chan, L L / Tan, L C S / Tan, E K. ·Department of Research, National Neuroscience Institute, Singapore, Singapore. · Department of Diagnostic Radiology, Singapore General Hospital, Singapore, Singapore. · Duke - National University of Singapore Graduate Medical School, Singapore, Singapore. · Department of Neurology, National Neuroscience Institute, Singapore. ·Eur J Neurol · Pubmed #27141858.

ABSTRACT: Depression, anxiety and apathy are common mood disturbances in Parkinson's disease (PD) but their pathophysiology is unclear. Advanced neuroimaging has been increasingly used to unravel neural substrates linked to these disturbances. A systematic review is provided of neuroimaging findings in depression, anxiety and apathy in PD. A PubMed, MEDLINE and EMBASE search of peer-reviewed original research articles on these mood disturbances in PD identified 38 studies on depression, eight on anxiety and 14 on apathy in PD. Most of the imaging studies used either position emission tomography or single-photon emission computed tomography techniques. These studies generally suggest increased neural activity in the prefrontal regions and decreased functional connectivity between the prefrontal-limbic networks in depressed patients. Functional imaging studies revealed an inverse correlation between dopaminergic density in the caudate and putamen with the severity of anxiety in PD. There was no consistent correlation between dopaminergic density of thalamus and anxiety. Studies demonstrated both positive and inverse correlations between apathy and metabolism or activity in the striatum, amygdalar, prefrontal, temporal and parietal regions. The clinical variability of study subjects and differences in image pre-processing and analytical strategies may contribute to discrepant findings in these studies. Both nigrostriatal and extra-nigrostriatal pathways (in particular the frontal region and its connecting areas) are affected in mood disorders in PD. Identifying the relative contributions of these neural pathways in PD patients with overlapping motor and mood symptoms could provide new pathophysiological clues for the development of better therapeutic targets for affected patients.

18 Review Linking F-box protein 7 and parkin to neuronal degeneration in Parkinson's disease (PD). 2016

Zhou, Zhi Dong / Sathiyamoorthy, Sushmitha / Angeles, Dario C / Tan, Eng King. ·National Neuroscience Institute of Singapore, 11 Jalan Tan Tock Seng, Singapore, 308433, Singapore. zhidong_zhou@nni.com.sg. · Signature Research Program in Neuroscience and Behavioural Disorders, Duke-NUS Graduate Medical School Singapore, 8 College Road, Singapore, 169857, Singapore. zhidong_zhou@nni.com.sg. · National Neuroscience Institute of Singapore, 11 Jalan Tan Tock Seng, Singapore, 308433, Singapore. · Department of Neurology, Singapore General Hospital, Outram Road, Singapore, 169608, Singapore. · National Neuroscience Institute of Singapore, 11 Jalan Tan Tock Seng, Singapore, 308433, Singapore. Tan.eng.king@sgh.com.sg. · Department of Neurology, Singapore General Hospital, Outram Road, Singapore, 169608, Singapore. Tan.eng.king@sgh.com.sg. · Signature Research Program in Neuroscience and Behavioural Disorders, Duke-NUS Graduate Medical School Singapore, 8 College Road, Singapore, 169857, Singapore. Tan.eng.king@sgh.com.sg. ·Mol Brain · Pubmed #27090516.

ABSTRACT: Mutations of F-box protein 7 (FBXO7) and Parkin, two proteins in ubiquitin-proteasome system (UPS), are both implicated in pathogenesis of dopamine (DA) neuron degeneration in Parkinson's disease (PD). Parkin is a HECT/RING hybrid ligase that physically receives ubiquitin on its catalytic centre and passes ubiquitin onto its substrates, whereas FBXO7 is an adaptor protein in Skp-Cullin-F-box (SCF) SCF(FBXO7) ubiquitin E3 ligase complex to recognize substrates and mediate substrates ubiquitination by SCF(FBXO7) E3 ligase. Here, we discuss the overlapping pathophysiologic mechanisms and clinical features linking Parkin and FBXO7 with autosomal recessive PD. Both proteins play an important role in neuroprotective mitophagy to clear away impaired mitochondria. Parkin can be recruited to impaired mitochondria whereas cellular stress can promote FBXO7 mitochondrial translocation. PD-linked FBXO7 can recruit Parkin into damaged mitochondria and facilitate its aggregation. WT FBXO7, but not PD-linked FBXO7 mutants can rescue DA neuron degeneration in Parkin null Drosophila. A better understanding of the common pathophysiologic mechanisms of these two proteins could unravel specific pathways for targeted therapy in PD.

19 Review Induced pluripotent stem cells in Parkinson's disease: scientific and clinical challenges. 2016

Xiao, Bin / Ng, Huck Hui / Takahashi, Ryosuke / Tan, Eng-King. ·National Neuroscience Institute, Singapore, Singapore. · Genome Institute of Singapore, Singapore, Singapore Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore, Singapore. · Department of Neurology, Kyoto University Graduate School of Medicine, Kyoto, Japan. · National Neuroscience Institute, Singapore, Singapore Genome Institute of Singapore, Singapore, Singapore Department of Neurology, Singapore General Hospital, Singapore, Singapore Duke-NUS Graduate Medical School, Singapore, Singapore. ·J Neurol Neurosurg Psychiatry · Pubmed #26833176.

ABSTRACT: Induced pluripotent stem cells (iPSCs), which greatly circumvent the ethical issue of human embryonic stem cells (ESCs), can be induced to differentiate to dopaminergic (DA) neurons, and hence be used as a human disease model for Parkinson's disease (PD). iPSCs can be also utilised to probe the mechanism, and serve as an 'in vivo' platform for drug screening and for cell-replacement therapies. However, any clinical trial approaches should be extensively supported by validated robust biological evidence (based on previous experience with fetal mesencephalic transplantation), in particular, the production and selection of the 'ideal' neurons (functional units with no oncological risk), together with the careful screening of appropriate candidates (such as genetic carriers), with inbuilt safeguards (safety studies) in the evaluation and monitoring (functional neuroimaging of both DA and non-DA system) of trial subjects. While iPSCs hold great promise for PD, there are still numerous scientific and clinical challenges that need to be surmounted before any clinical application can be safely introduced.

20 Review microRNAs and Neurodegenerative Diseases. 2015

Qiu, Lifeng / Tan, Eng King / Zeng, Li. ·Neural Stem Cell Research Lab, Department of Research, National Neuroscience Institute, Singapore, 308433, Singapore. · Department of Neurology, National Neuroscience Institute, SGH Campus, Singapore, 169856, Singapore. · Department of Research, National Neuroscience Institute, 11 Jalan Tan Tock Seng, Singapore, 308433, Singapore. · Neuroscience and Behavioral Disorders program, Duke-National University of Singapore, Graduate Medical School, Singapore, 169857, Singapore. · Neural Stem Cell Research Lab, Department of Research, National Neuroscience Institute, Singapore, 308433, Singapore. Li_ZENG@nni.com.sg. · Department of Research, National Neuroscience Institute, 11 Jalan Tan Tock Seng, Singapore, 308433, Singapore. Li_ZENG@nni.com.sg. · Neuroscience and Behavioral Disorders program, Duke-National University of Singapore, Graduate Medical School, Singapore, 169857, Singapore. Li_ZENG@nni.com.sg. ·Adv Exp Med Biol · Pubmed #26663180.

ABSTRACT: microRNAs (miRNAs) are small, noncoding RNA molecules that through imperfect base-pairing with complementary sequences of target mRNA molecules, typically cleave target mRNA, causing subsequent degradation or translation inhibition. Although an increasing number of studies have identified misregulated miRNAs in the neurodegenerative diseases (NDDs) Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, which suggests that alterations in the miRNA regulatory pathway could contribute to disease pathogenesis, the molecular mechanisms underlying the pathological implications of misregulated miRNA expression and the regulation of the key genes involved in NDDs remain largely unknown. In this chapter, we provide evidence of the function and regulation of miRNAs and their association with the neurological events in NDDs. This will help improve our understanding of how miRNAs govern the biological functions of key pathogenic genes in these diseases, which potentially regulate several pathways involved in the progression of neurodegeneration. Additionally, given the growing interest in the therapeutic potential of miRNAs, we discuss current clinical challenges to developing miRNA-based therapeutics for NDDs.

21 Review Nonmotor symptoms in sporadic versus familial forms of Parkinson's disease. 2015

Chao, Yin Xia / Chew, Lai Mun / Deng, Xiao / Tan, Eng-King. ·National Neuroscience Institute, Singapore 308433, Singapore. ·Neurodegener Dis Manag · Pubmed #25894878.

ABSTRACT: Besides the classical motor symptoms, Parkinson's disease (PD) patients experience a wide range of nonmotor symptoms (NMS) throughout the disease course. However, due to the lack of recognition and understanding of the pathogenesis, NMS symptoms may be overlooked. Familial PD is a well-defined group that can provide a good model to investigate the mechanisms for both motor and NMS in PD. Some studies suggest that the frequency of NMS is not different between genetic and sporadic form of PD while others suggest that specific domains (such as neuropsychiatric symptoms) are more common in the genetic form. Early recognition of NMS may facilitate early diagnosis and monitoring of both sporadic and genetic PD.

22 Review Deciphering the function and regulation of microRNAs in Alzheimer's disease and Parkinson's disease. 2014

Qiu, Lifeng / Zhang, Wei / Tan, Eng King / Zeng, Li. ·Neural Stem Cell Research Lab, Research Department, National Neuroscience Institute , 308433, Singapore. ·ACS Chem Neurosci · Pubmed #25210999.

ABSTRACT: MicroRNAs (miRNAs) are single stranded, noncoding RNA molecules that are encoded by eukaryotic nuclear DNA. miRNAs function through imperfect base-pairing with complementary sequences of target mRNA molecules, which is typically via the cleavage of target mRNA with transcriptional repression or translational degradation. An increasing number of studies identified dysregulation of miRNAs in neurodegenerative disease and suggest that alterations in the miRNA regulatory pathway could contribute to the disease pathogenesis. However, molecular mechanisms underlying the pathological implications of dysregulated miRNA expression and regulation of the key genes that are involved in neurodegenerative diseases remain largely unknown. Here, we review the evidence for the functional role of dysregulated miRNAs involved in disease pathogenesis, as well as how miRNAs govern neuronal functions either upstream or downstream of target genes that are disease pathogenic factors. Furthermore, we review the cellular feedback regulation between miRNAs and target genes in neurodegenerative diseases, with a focus on Alzheimer's disease and Parkinson's disease.

23 Review Evidence of inflammatory system involvement in Parkinson's disease. 2014

Chao, Yinxia / Wong, Siew Cheng / Tan, Eng King. ·National Neuroscience Institute, Singapore 308433 ; Duke-National University of Singapore Graduate Medical School, Singapore 169857. · Singapore Immunology Network, Agency for Science, Technology and Research, Singapore 138648 ; Department of Microbiology, National University of Singapore, Singapore 117545. · National Neuroscience Institute, Singapore 308433 ; Duke-National University of Singapore Graduate Medical School, Singapore 169857 ; Department of Neurology, Singapore General Hospital, Singapore 169608 ; Department of Neurology, National Neuroscience Institute (SGH Campus), 20 College Road, Academia Level 4, Singapore 169856. ·Biomed Res Int · Pubmed #25050341.

ABSTRACT: Parkinson's disease (PD) is a chronic neurodegenerative disease underpinned by both genetic and environmental etiologic factors. Recent findings suggest that inflammation may be a pathogenic factor in the onset and progression of both familial and sporadic PD. Understanding the precise role of inflammatory factors in PD will likely lead to understanding of how the disease arises. In vivo evidence for inflammation in PD includes dysregulated molecular mediators such as cytokines, complement system and its receptors, resident microglial activation, peripheral immune cells invasion, and altered composition and phenotype of peripheral immune cells. The growing awareness of these factors has prompted novel approaches to modulate the immune system, although it remains whether these approaches can be used in humans. Influences of ageing and differential exposure to environmental agents suggest potential host-pathogen specific pathophysiologic factors. There is a clear need for research to further unravel the pathophysiologic role of immunity in PD, with the potential of developing new therapeutic targets for this debilitating condition.

24 Review Genetic testing of LRRK2 in Parkinson's disease: is there a clinical role? 2014

Buhat, Donna Mae Lyn / Tan, Eng-King. ·Department of Neurology, National Neuroscience Institute, Singapore. ·Parkinsonism Relat Disord · Pubmed #24262189.

ABSTRACT: Genetic testing has played an important role for the diagnosis of many rare monogenic disorders. However, the role and limitations of genetic testing have generated considerable debate in the medical community. In recent years, the identification of several monogenic genes in Parkinson's disease (PD), a common neurodegenerative disorder, has led to calls for genetic testing guidelines for this disorder. Genetic testing of LRRK2 provides an excellent platform to highlight some of the pertinent issues (generic and specific) related to genetic testing in PD. The identification of a common recurrent mutation (G2019S) worldwide provides an opportunity for developing guidelines that are applicable internationally. However, the incomplete penetrance of the mutation and the lack of clarity of the pathogenicity of many other reported LRRK2 mutations call for cautious implementation of genetic testing programs. The clinical utility of genetic testing is compounded by easy accessibility of Direct to Consumer genetic services and the relative lack of regulation on reliability of service providers in internet advertisements. Based on current literature, genetic testing of LRRK2 (particularly for G2019S) certainly has a clinical role, though it is applicable primarily in select scenarios and in certain at-risk populations.

25 Review Targeting leucine-rich repeat kinase 2 in Parkinson's disease. 2013

Chan, Sharon L / Angeles, Dario C / Tan, Eng-King. ·National Neuroscience Institute , SGH Campus , Singapore. ·Expert Opin Ther Targets · Pubmed #24206363.

ABSTRACT: INTRODUCTION: Parkinson's disease (PD), is a common progressive neurodegenerative disorder, and missense mutations in the LRRK2 gene are the most common single genetic cause of autosomal dominant PD and polymorphic variants modulate risk in sporadic PD. Earlier research focused on LRRK2 genetics, but with the recent discoveries of LRRK2 substrates/interactors, LRRK2-specific mechanisms are being unveiled. AREAS COVERED: As a multi-domain protein, LRRK2 possess diverse functions that range from housekeeping, signaling to clearance of proteins. Proteins that interact with LRRK2 have drawn attention to several pathophysiologic pathways that could potentially be targeted in the development of new therapies. This review will discuss the possible physiological roles of LRRK2 based on recently reported interactors as well as place LRRK2 in the disease context. Current LRRK2 inhibition studies and reports about LRRK2 biomarkers will also be discussed as they are important considerations for LRRK2 translational treatment options. EXPERT OPINION: The discovery of LRRK2 as a pathogenic gene in PD has contributed enormously to our understanding of clinical genetics. One of the challenges is to understand the physiologic role of LRRK2 and its specific function that gets disrupted when it is mutated. In vivo LRRK2 models have provided insights but they do not full recapitulate human PD. The identification of LRRK2 interactors opens the opportunities for identification of new therapeutic targets. Ways of quantification of kinase activity in vivo and determining what constitutes physiologic inhibition will need to be further investigated before specific pharmacologic agents can be meaningfully utilized.

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