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Parkinson Disease: HELP
Articles by Sudhakar Raja Subramaniam
Based on 7 articles published since 2010
(Why 7 articles?)
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Between 2010 and 2020, S. R. Subramaniam wrote the following 7 articles about Parkinson Disease.
 
+ Citations + Abstracts
1 Review Targeting Microglial Activation States as a Therapeutic Avenue in Parkinson's Disease. 2017

Subramaniam, Sudhakar R / Federoff, Howard J. ·Department of Neurology, University of California, Irvine, Irvine, CAUnited States. ·Front Aging Neurosci · Pubmed #28642697.

ABSTRACT: Parkinson's disease (PD) is a chronic and progressive disorder characterized neuropathologically by loss of dopamine neurons in the substantia nigra, intracellular proteinaceous inclusions, reduction of dopaminergic terminals in the striatum, and increased neuroinflammatory cells. The consequent reduction of dopamine in the basal ganglia results in the classical parkinsonian motor phenotype. A growing body of evidence suggest that neuroinflammation mediated by microglia, the resident macrophage-like immune cells in the brain, play a contributory role in PD pathogenesis. Microglia participate in both physiological and pathological conditions. In the former, microglia restore the integrity of the central nervous system and, in the latter, they promote disease progression. Microglia acquire different activation states to modulate these cellular functions. Upon activation to the M1 phenotype, microglia elaborate pro-inflammatory cytokines and neurotoxic molecules promoting inflammation and cytotoxic responses. In contrast, when adopting the M2 phenotype microglia secrete anti-inflammatory gene products and trophic factors that promote repair, regeneration, and restore homeostasis. Relatively little is known about the different microglial activation states in PD and a better understanding is essential for developing putative neuroprotective agents. Targeting microglial activation states by suppressing their deleterious pro-inflammatory neurotoxicity and/or simultaneously enhancing their beneficial anti-inflammatory protective functions appear as a valid therapeutic approach for PD treatment. In this review, we summarize microglial functions and, their dual neurotoxic and neuroprotective role in PD. We also review molecules that modulate microglial activation states as a therapeutic option for PD treatment.

2 Review Mitochondrial dysfunction and oxidative stress in Parkinson's disease. 2013

Subramaniam, Sudhakar Raja / Chesselet, Marie-Francoise. ·Department of Neurology, David Geffen School of Medicine, UCLA, 710 Westwood Plaza, Los Angeles, CA 90095-1769, USA. ·Prog Neurobiol · Pubmed #23643800.

ABSTRACT: Parkinson's disease (PD) is a movement disorder that is characterized by the progressive degeneration of dopaminergic neurons in substantia nigra pars compacta resulting in dopamine deficiency in the striatum. Although majority of the PD cases are sporadic several genetic mutations have also been linked to the disease thus providing new opportunities to study the pathology of the illness. Studies in humans and various animal models of PD reveal that mitochondrial dysfunction might be a defect that occurs early in PD pathogenesis and appears to be a widespread feature in both sporadic and monogenic forms of PD. The general mitochondrial abnormalities linked with the disease include mitochondrial electron transport chain impairment, alterations in mitochondrial morphology and dynamics, mitochondrial DNA mutations and anomaly in calcium homeostasis. Mitochondria are vital organelles with multiple functions and their dysfunction can lead to a decline in energy production, generation of reactive oxygen species and induction of stress-induced apoptosis. In this review, we give an outline of mitochondrial functions that are affected in the pathogenesis of sporadic and familial PD, and hence provide insights that might be valuable for focused future research to exploit possible mitochondrial targets for neuroprotective interventions in PD.

3 Review A progressive mouse model of Parkinson's disease: the Thy1-aSyn ("Line 61") mice. 2012

Chesselet, Marie-Francoise / Richter, Franziska / Zhu, Chunni / Magen, Iddo / Watson, Melanie B / Subramaniam, Sudhakar R. ·Department of Neurology, David Geffen School of Medicine, UCLA, Los Angeles, California 90095, USA. MChesselet@mednet.ucla.edu ·Neurotherapeutics · Pubmed #22350713.

ABSTRACT: Identification of mutations that cause rare familial forms of Parkinson's disease (PD) and subsequent studies of genetic risk factors for sporadic PD have led to an improved understanding of the pathological mechanisms that may cause nonfamilial PD. In particular, genetic and pathological studies strongly suggest that alpha-synuclein, albeit very rarely mutated in PD patients, plays a critical role in the vast majority of individuals with the sporadic form of the disease. We have extensively characterized a mouse model over-expressing full-length, human, wild-type alpha-synuclein under the Thy-1 promoter. We have also shown that this model reproduces many features of sporadic PD, including progressive changes in dopamine release and striatal content, alpha-synuclein pathology, deficits in motor and nonmotor functions that are affected in pre-manifest and manifest phases of PD, inflammation, and biochemical and molecular changes similar to those observed in PD. Preclinical studies have already demonstrated improvement with promising new drugs in this model, which provides an opportunity to test novel neuroprotective strategies during different phases of the disorder using endpoint measures with high power to detect drug effects.

4 Article Chronic nicotine improves cognitive and social impairment in mice overexpressing wild type α-synuclein. 2018

Subramaniam, Sudhakar R / Magen, Iddo / Bove, Nicholas / Zhu, Chunni / Lemesre, Vincent / Dutta, Garima / Elias, Chris Jean / Lester, Henry A / Chesselet, Marie-Francoise. ·Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA. Electronic address: sudhakar.subramaniam@uci.edu. · Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA. · Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA. · Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA. Electronic address: mchesselet@mednet.ucla.edu. ·Neurobiol Dis · Pubmed #29859873.

ABSTRACT: In addition to dopaminergic and motor deficits, patients with Parkinson's disease (PD) suffer from non-motor symptoms, including early cognitive and social impairment, that do not respond well to dopaminergic therapy. Cholinergic deficits may contribute to these problems, but cholinesterase inhibitors have limited efficacy. Mice over-expressing α-synuclein, a protein critically associated with PD, show deficits in cognitive and social interaction tests, as well as a decrease in cortical acetylcholine. We have evaluated the effects of chronic administration of nicotine in mice over-expressing wild type human α-synuclein under the Thy1-promoter (Thy1-aSyn mice). Nicotine was administered subcutaneously by osmotic minipump for 6 months from 2 to 8 months of age at 0.4 mg/kg/h and 2.0 mg/kg/h. The higher dose was toxic in the Thy1-aSyn mice, but the low dose was well tolerated and both doses ameliorated cognitive impairment in Y-maze performance after 5 months of treatment. In a separate cohort of Thy1-aSyn mice, nicotine was administered at the lower dose for one month beginning at 5 months of age. This treatment partially eliminated the cognitive deficit in novel object recognition and social impairment. In contrast, chronic nicotine did not improve motor deficits after 2, 4 or 6 months of treatment, nor modified α-synuclein aggregation, tyrosine hydroxylase immunostaining, synaptic and dendritic markers, or microglial activation in Thy1-aSyn mice. These results suggest that cognitive and social impairment in synucleinopathies like PD may result from deficits in cholinergic neurotransmission and may benefit from chronic administration of nicotinic agonists.

5 Article A Molecular Tweezer Ameliorates Motor Deficits in Mice Overexpressing α-Synuclein. 2017

Richter, Franziska / Subramaniam, Sudhakar R / Magen, Iddo / Lee, Patrick / Hayes, Jane / Attar, Aida / Zhu, Chunni / Franich, Nicholas R / Bove, Nicholas / De La Rosa, Krystal / Kwong, Jacky / Klärner, Frank-Gerrit / Schrader, Thomas / Chesselet, Marie-Françoise / Bitan, Gal. ·Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. · Brain Research Institute, University of California, Los Angeles, Los Angeles, CA, USA. · Institute of Organic Chemistry, University of Duisburg-Essen, Essen, Germany. · Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. mchesselet@mednet.ucla.edu. · Brain Research Institute, University of California, Los Angeles, Los Angeles, CA, USA. mchesselet@mednet.ucla.edu. · Department of Neurobiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. mchesselet@mednet.ucla.edu. · Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, USA. mchesselet@mednet.ucla.edu. · Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. gbitan@mednet.ucla.edu. · Brain Research Institute, University of California, Los Angeles, Los Angeles, CA, USA. gbitan@mednet.ucla.edu. · Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, USA. gbitan@mednet.ucla.edu. ·Neurotherapeutics · Pubmed #28585223.

ABSTRACT: Aberrant accumulation and self-assembly of α-synuclein are tightly linked to several neurodegenerative diseases called synucleinopathies, including idiopathic Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. Deposition of fibrillar α-synuclein as insoluble inclusions in affected brain cells is a pathological hallmark of synucleinopathies. However, water-soluble α-synuclein oligomers may be the actual culprits causing neuronal dysfunction and degeneration in synucleinopathies. Accordingly, therapeutic approaches targeting the toxic α-synuclein assemblies are attractive for these incurable disorders. The "molecular tweezer" CLR01 selectively remodels abnormal protein self-assembly through reversible binding to Lys residues. Here, we treated young male mice overexpressing human wild-type α-synuclein under control of the Thy-1 promoter (Thy1-aSyn mice) with CLR01 and examined motor behavior and α-synuclein in the brain. Intracerebroventricular administration of CLR01 for 28 days to the mice improved motor dysfunction in the challenging beam test and caused a significant decrease of buffer-soluble α-synuclein in the striatum. Proteinase-K-resistant, insoluble α-synuclein deposits remained unchanged in the substantia nigra, whereas levels of diffuse cytoplasmic α-synuclein in dopaminergic neurons increased in mice receiving CLR01 compared with vehicle. More moderate improvement of motor deficits was also achieved by subcutaneous administration of CLR01, in 2/5 trials of the challenging beam test and in the pole test, which requires balance and coordination. The data support further development of molecular tweezers as therapeutic agents for synucleinopathies.

6 Article Neuroprotective effects of umbelliferone and esculetin in a mouse model of Parkinson's disease. 2013

Subramaniam, Sudhakar R / Ellis, Elizabeth M. ·Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, United Kingdom. ·J Neurosci Res · Pubmed #23184853.

ABSTRACT: The production of reactive oxygen species and mitochondrial dysfunction in the brain are both associated with the progression of several neurodegenerative diseases, including Parkinson's disease. These characteristics are also observed when rodents are exposed to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a compound that causes nigrostriatal dopaminergic neurotoxicity and that has been used previously for assessing the effectiveness of neuroprotective agents. In this study, the neuroprotective effects of two coumarins, umbelliferone and esculetin, against MPTP-induced neurotoxicity were examined in C57BL/6J mice. The results show that dietary administration of umbelliferone and esculetin significantly attenuated MPTP-induced neurotoxicity in the substantia nigra pars compacta but not striatum, as measured by tyrosine hydroxylase staining. Both coumarins also prevented an MPTP-induced increase in nitrosative stress as measured by 3-nitrotyrosine immunoreactivity and also maintained glutathione levels in MPTP-exposed mice as well as in cell lines exposed to the metabolite 1-methyl-4-phenylpyridinium. Umbelliferone and esculetin also prevented MPTP-dependent caspase 3 activation, an indicator of apoptosis, but did not inhibit monoamine oxidase activity. This is the first time that the neuroprotective capabilities of these coumarins have been demonstrated, and the results indicate that umbelliferone and esculetin can protect against MPTP-induced neurotoxicity in the mouse. These compounds can cross the blood-brain barrier, so their effectiveness indicates that they have the potential to protect in neurodegenerative disease such as Parkinson's disease.

7 Article Mice overexpressing wild-type human alpha-synuclein display alterations in colonic myenteric ganglia and defecation. 2012

Wang, L / Magen, I / Yuan, P-Q / Subramaniam, S R / Richter, F / Chesselet, M-F / Taché, Y. ·CURE: Digestive Diseases Research Center and Center for Neurobiology of Stress, Department of Medicine, Division of Digestive Diseases, David Geffen School of Medicine, University of California Los Angeles and Veteran Affairs Greater Los Angeles Healthcare System, Los Angeles, USA. lixinw@ucla.edu ·Neurogastroenterol Motil · Pubmed #22779732.

ABSTRACT: BACKGROUND: Prevalent non-motor symptoms of Parkinson's disease (PD) include gastrointestinal motor impairments and advanced stage PD displays pathological aggregates of α-synuclein in colonic enteric neurons. We previously showed that 12 months old mice overexpressing human wild type (WT) α-synuclein under the Thy1 promoter (Thy1-aSyn) displayed colonic motor dysfunction. We investigated functional gut alterations at earlier ages and histological correlates. METHODS: Defecation, gastric emptying (GE), and immunostaining for α-synuclein, peripheral choline acetyltransferase (pChAT), tyrosine hydroxylase (TH), neuronal nitric oxide synthase (nNOS), and vasoactive intestinal peptide (VIP) in distal colon myenteric plexuses were assessed in male Thy1-aSyn compared to littermate WT mice. KEY RESULTS: Thy1-aSyn mice aged 2.5-3 or 7-8 months old had 81% and 55% reduction in fecal pellet output, respectively, in the first 15 min of exposure to a novel environment. The reduction remained significant in the older group for 2-h, and subsequent refeeding resulted also in a 60% and 69% reduction of defecation in the first hour, respectively. Thy1-aSyn mice (8-10 months) displayed increased α-synuclein in the myenteric plexuses with abundant varicose terminals surrounding pChAT-immunoreactive (ir) neurons, and only a few, nNOS-ir neurons. There were no conspicuous changes in pChAT- and nNOS-ir neurons, or TH- and VIP-ir nerve fibers. Thy1-aSyn mice aged 4-18 months had normal GE. CONCLUSIONS & INFERENCES: The occurrence of over-production of pre-synaptic α-synuclein in colonic myenteric ganglia several months before the loss of striatal dopamine may provide an anatomical basis for interference with cholinergic neuronal activation, causing an early impairment in defecation to stimuli.