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1.
Iron promotes α‐synuclein aggregation and transmission by inhibiting TFEB‐mediated autophagosome‐lysosome fusion 下载免费PDF全文
Yousheng Xiao Xiang Chen Shuxuan Huang Guihua Li Mingshu Mo Li Zhang Chaojun Chen Wenyuan Guo Miaomiao Zhou Zhuohua Wu Luan Cen Simei Long Shaomin Li Xinling Yang Shaogang Qu Zhong Pei Pingyi Xu 《Journal of neurochemistry》2018,145(1):34-50
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Ernesto Villanueva Haiyan Lou Tshianda N. M. Alerte Eloise Peet Robert E. Drolet Ruth G. Perez 《Journal of neurochemistry》2014,128(4):536-546
Aging, the main risk factor for Parkinson's disease (PD), is associated with increased α–synuclein levels in substantia nigra pars compacta (SNc). Excess α‐synuclein spurs Lewy‐like pathology and dysregulates the activity of protein phosphatase 2A (PP2A). PP2A dephosphorylates many neuroproteins, including the catecholamine rate‐limiting enzyme, tyrosine hydroxylase (TH). A loss of nigral dopaminergic neurons induces PD movement problems, but before those abnormalities occur, behaviors such as olfactory loss, anxiety, and constipation often manifest. Identifying mouse models with early PD behavioral changes could provide a model in which to test emerging therapeutic compounds. To this end, we evaluated mice expressing A53T mutant human (A53T) α–synuclein for behavior and α–synuclein pathology in olfactory bulb, adrenal gland, and gut. Aging A53T mice exhibited olfactory loss and anxiety that paralleled olfactory and adrenal α‐synuclein aggregation. PP2A activity was also diminished in olfactory and adrenal tissues harboring insoluble α‐synuclein. Low adrenal PP2A activity co‐occurred with TH hyperactivity, making this the first study to link adrenal synucleinopathy to anxiety and catecholamine dysregulation. Aggregated A53T α–synuclein recombinant protein also had impaired stimulatory effects on soluble recombinant PP2A. Collectively, the data identify an excellent model in which to screen compounds for their ability to block the spread of α‐synuclein pathology associated with pre‐motor stages of PD.
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Xinni Luo Le Hou Haishan Shi Xiaomei Zhong Yufeng Zhang Dong Zheng Yan Tan Guoyan Hu Nan Mu Jianping Chan Xinru Chen Yaxiu Fang Fengchun Wu Hongbo He Yuping Ning 《Journal of neurochemistry》2013,127(5):681-690
The overlapping clinical features of Alzheimer's disease (AD) and Dementia with Lewy bodies (DLB) make differentiation difficult in the clinical environment. Evaluating the CSF levels of biomarkers in AD and DLB patients could facilitate clinical diagnosis. CSF Visinin‐like protein‐1 (VILIP‐1), a calcium‐mediated neuronal injury biomarker, has been described as a novel biomarker for AD. The aim of this study was to investigate the diagnostic utility of CSF VILIP‐1 and VILIP‐1/Aβ1–42 ratio to distinguish AD from DLB. Levels of CSF VILIP‐1, t‐tau, p‐tau181P, Aβ1–42, and α‐synuclein were measured in 61 AD patients, 32 DLB patients, and 40 normal controls using commercial ELISA kits. The results showed that the CSF VILIP‐1 level had significantly increased in AD patients compared with both normal controls and DLB patients. The CSF VILIP‐1 and VILIP‐1/Aβ1–42 levels had enough diagnostic accuracy to allow the detection and differential diagnosis of AD. Additionally, CSF VILIP‐1 levels were positively correlated with t‐tau and p‐tau181P within each group and with α‐synuclein in the AD and control groups. We conclude that CSF VILIP‐1 could be a diagnostic marker for AD, differentiating it from DLB. The analysis of biomarkers, representing different neuropathologies, is an important approach reflecting the heterogeneous features of AD and DLB.
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Donna Crabtree Matthew Dodson Xiaosen Ouyang Michaël Boyer‐Guittaut Qiuli Liang Mary E. Ballestas Naomi Fineberg Jianhua Zhang 《Journal of neurochemistry》2014,128(6):950-961
Parkinson's disease is a neurodegenerative movement disorder. The histopathology of Parkinson's disease comprises proteinaceous inclusions known as Lewy bodies, which contains aggregated α‐synuclein. Cathepsin D (CD) is a lysosomal protease previously demonstrated to cleave α‐synuclein and decrease its toxicity in both cell lines and mouse brains in vivo. Here, we show that pharmacological inhibition of CD, or introduction of catalytically inactive mutant CD, resulted in decreased CD activity and increased cathepsin B activity, suggesting a possible compensatory response to inhibition of CD activity. However, this increased cathepsin B activity was not sufficient to maintain α‐synuclein degradation, as evidenced by the accumulation of endogenous α‐synuclein. Interestingly, the levels of LC3, LAMP1, and LAMP2, proteins involved in autophagy‐lysosomal activities, as well as total lysosomal mass as assessed by LysoTracker flow cytometry, were unchanged. Neither autophagic flux nor proteasomal activities differs between cells over‐expressing wild‐type versus mutant CD. These observations point to a critical regulatory role for that endogenous CD activity in dopaminergic cells in α‐synuclein homeostasis which cannot be compensated for by increased Cathepsin B. These data support the potential need to enhance CD function in order to attenuate α‐synuclein accumulation as a therapeutic strategy against development of synucleinopathy.
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Carola Rotermund Felicia M. Truckenmüller Heinrich Schell Philipp J. Kahle 《Journal of neurochemistry》2014,131(6):848-858
Parkinson's disease (PD) and diabetes belong to the most common neurodegenerative and metabolic syndromes, respectively. Epidemiological links between these two frequent disorders are controversial. The neuropathological hallmarks of PD are protein aggregates composed of amyloid‐like fibrillar and serine‐129 phosphorylated (pS129) α‐synuclein (AS). To study if diet‐induced obesity could be an environmental risk factor for PD‐related α‐synucleinopathy, transgenic (TG) mice, expressing the human mutant A30P AS in brain neurons, were subjected after weaning to a lifelong high fat diet (HFD). The TG mice became obese and glucose‐intolerant, as did the wild‐type controls. Upon aging, HFD significantly accelerated the onset of the lethal locomotor phenotype. Coinciding with the premature movement phenotype and death, HFD accelerated the age of onset of brainstem α‐synucleinopathy as detected by immunostaining with antibodies against pathology‐associated pS129. Amyloid‐like neuropathology was confirmed by thioflavin S staining. Accelerated onset of neurodegeneration was indicated by Gallyas silver‐positive neuronal dystrophy as well as astrogliosis. Phosphorylation of the activation sites of the pro‐survival signaling intermediate Akt was reduced in younger TG mice after HFD. Thus, diet‐induced obesity may be an environmental risk factor for the development of α‐synucleinopathies. The molecular and cellular mechanisms remain to be further elucidated.
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Plamena R. Angelova Mathew H. Horrocks David Klenerman Sonia Gandhi Andrey Y. Abramov Mikhail S. Shchepinov 《Journal of neurochemistry》2015,133(4):582-589
Parkinson's disease is the second most common neurodegenerative disease and its pathogenesis is closely associated with oxidative stress. Deposition of aggregated α‐synuclein (α‐Syn) occurs in familial and sporadic forms of Parkinson's disease. Here, we studied the effect of oligomeric α‐Syn on one of the major markers of oxidative stress, lipid peroxidation, in primary co‐cultures of neurons and astrocytes. We found that oligomeric but not monomeric α‐Syn significantly increases the rate of production of reactive oxygen species, subsequently inducing lipid peroxidation in both neurons and astrocytes. Pre‐incubation of cells with isotope‐reinforced polyunsaturated fatty acids (D‐PUFAs) completely prevented the effect of oligomeric α‐Syn on lipid peroxidation. Inhibition of lipid peroxidation with D‐PUFAs further protected cells from cell death induced by oligomeric α‐Syn. Thus, lipid peroxidation induced by misfolding of α‐Syn may play an important role in the cellular mechanism of neuronal cell loss in Parkinson's disease.
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Aritri Bir Oishimaya Sen Shruti Anand Vineet Kumar Khemka Priyanjalee Banerjee Roberto Cappai Arghyadip Sahoo Sasanka Chakrabarti 《Journal of neurochemistry》2014,131(6):868-877
This study has shown that purified recombinant human α‐synuclein (20 μM) causes membrane depolarization and loss of phosphorylation capacity of isolated purified rat brain mitochondria by activating permeability transition pore complex. In intact SHSY5Y (human neuroblastoma cell line) cells, lactacystin (5 μM), a proteasomal inhibitor, causes an accumulation of α‐synuclein with concomitant mitochondrial dysfunction and cell death. The effects of lactacystin on intact SHSY5Y cells are, however, prevented by knocking down α‐synuclein expression by specific siRNA. Furthermore, in wild‐type (non‐transfected) SHSY5Y cells, the effects of lactacystin on mitochondrial function and cell viability are also prevented by cyclosporin A (1 μM) which blocks the activity of the mitochondrial permeability transition pore. Likewise, in wild‐type SHSY5Y cells, typical mitochondrial poison like antimycin A (50 nM) produces loss of cell viability comparable to that of lactacystin (5 μM). These data, in combination with those from isolated brain mitochondria, strongly suggest that intracellularly accumulated α‐synuclein can interact with mitochondria in intact SHSY5Y cells causing dysfunction of the organelle which drives the cell death under our experimental conditions. The results have clear implications in the pathogenesis of sporadic Parkinson's disease.
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Yuval Nash Eran Schmukler Dorit Trudler Ronit Pinkas‐Kramarski Dan Frenkel 《Journal of neurochemistry》2017,143(5):584-594
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Eric D. Gaier Megan B. Miller Martina Ralle Dipendra Aryal William C. Wetsel Richard E. Mains Betty A. Eipper 《Journal of neurochemistry》2013,127(5):605-619
Copper (Cu), an essential trace element present throughout the mammalian nervous system, is crucial for normal synaptic function. Neuronal handling of Cu is poorly understood. We studied the localization and expression of Atp7a, the major intracellular Cu transporter in the brain, and its relation to peptidylglycine α‐amidating monooxygenase (PAM), an essential cuproenzyme and regulator of Cu homeostasis in neuroendocrine cells. Based on biochemical fractionation and immunostaining of dissociated neurons, Atp7a was enriched in post‐synaptic vesicular fractions. Cu followed a similar pattern, with ~ 20% of total Cu in synaptosomes. A mouse model heterozygous for the Pam gene (PAM+/?) was selectively Cu deficient in the amygdala. As in cortex and hippocampus, Atp7a and PAM expression overlap in the amygdala, with highest expression in interneurons. Messenger RNA levels of Atox‐1 and Atp7a, which deliver Cu to the secretory pathway, were reduced in the amygdala but not in the hippocampus in PAM+/? mice, GABAB receptor mRNA levels were similarly affected. Consistent with Cu deficiency, dopamine β‐monooxygenase function was impaired as evidenced by elevated dopamine metabolites in the amygdala, but not in the hippocampus, of PAM+/? mice. These alterations in Cu delivery to the secretory pathway in the PAM+/? amygdala may contribute to the physiological and behavioral deficits observed.
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Extracellular α‐synuclein alters synaptic transmission in brain neurons by perforating the neuronal plasma membrane 下载免费PDF全文
Carla R. Pacheco Camila N. Morales Alejandra E. Ramírez Francisco J. Muñoz Scarlet S. Gallegos Pablo A. Caviedes Luis G. Aguayo Carlos M. Opazo 《Journal of neurochemistry》2015,132(6):731-741
It has been postulated that the accumulation of extracellular α‐synuclein (α‐syn) might alter the neuronal membrane by formation of ‘pore‐like structures’ that will lead to alterations in ionic homeostasis. However, this has never been demonstrated to occur in brain neuronal plasma membranes. In this study, we show that α‐syn oligomers rapidly associate with hippocampal membranes in a punctate fashion, resulting in increased membrane conductance (5 fold over control) and the influx of both calcium and a fluorescent glucose analogue. The enhancement in intracellular calcium (1.7 fold over control) caused a large increase in the frequency of synaptic transmission (2.5 fold over control), calcium transients (3 fold over control), and synaptic vesicle release. Both primary hippocampal and dissociated nigral neurons showed rapid increases in membrane conductance by α‐syn oligomers. In addition, we show here that α‐syn caused synaptotoxic failure associated with a decrease in SV2, a membrane protein of synaptic vesicles associated with neurotransmitter release. In conclusion, extracellular α‐syn oligomers facilitate the perforation of the neuronal plasma membrane, thus explaining, in part, the synaptotoxicity observed in neurodegenerative diseases characterized by its extracellular accumulation.
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Assembly,trafficking and function of α1β2γ2 GABAA receptors are regulated by N‐terminal regions,in a subunit‐specific manner 下载免费PDF全文
GABAA receptors are pentameric ligand‐gated ion channels that mediate inhibitory fast synaptic transmission in the central nervous system. Consistent with recent pentameric ligand‐gated ion channels structures, sequence analysis predicts an α‐helix near the N‐terminus of each GABAA receptor subunit. Preceding each α‐helix are 8–36 additional residues, which we term the N‐terminal extension. In homomeric GABAC receptors and nicotinic acetylcholine receptors, the N‐terminal α‐helix is functionally essential. Here, we determined the role of the N‐terminal extension and putative α‐helix in heteromeric α1β2γ2 GABAA receptors. This role was most prominent in the α1 subunit, with deletion of the N‐terminal extension or further deletion of the putative α‐helix both dramatically reduced the number of functional receptors at the cell surface. Conversely, deletion of the β2 or γ2 N‐terminal extension had little effect on the number of functional cell surface receptors. Additional deletion of the putative α‐helix in the β2 or γ2 subunits did, however, decrease both functional cell surface receptors and incorporation of the γ2 subunit into mature receptors. In the β2 subunit only, α‐helix deletions affected GABA sensitivity and desensitization. Our findings demonstrate that N‐terminal extensions and α‐helices make key subunit‐specific contributions to assembly, consistent with both regions being involved in inter‐subunit interactions.
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Phenolic compounds prevent the oligomerization of α‐synuclein and reduce synaptic toxicity 下载免费PDF全文
Ryoichi Takahashi Kenjiro Ono Yusaku Takamura Mineyuki Mizuguchi Tokuhei Ikeda Hisao Nishijo Masahito Yamada 《Journal of neurochemistry》2015,134(5):943-955
Lewy bodies, mainly composed of α‐synuclein (αS), are pathological hallmarks of Parkinson's disease and dementia with Lewy bodies. Epidemiological studies showed that green tea consumption or habitual intake of phenolic compounds reduced Parkinson's disease risk. We previously reported that phenolic compounds inhibited αS fibrillation and destabilized preformed αS fibrils. Cumulative evidence suggests that low‐order αS oligomers are neurotoxic and critical species in the pathogenesis of α‐synucleinopathies. To develop disease modifying therapies for α‐synucleinopathies, we examined effects of phenolic compounds (myricetin (Myr), curcumin, rosmarinic acid (RA), nordihydroguaiaretic acid, and ferulic acid) on αS oligomerization. Using methods such as photo‐induced cross‐linking of unmodified proteins, circular dichroism spectroscopy, the electron microscope, and the atomic force microscope, we showed that Myr and RA inhibited αS oligomerization and secondary structure conversion. The nuclear magnetic resonance analysis revealed that Myr directly bound to the N‐terminal region of αS, whereas direct binding of RA to monomeric αS was not detected. Electrophysiological assays for long‐term potentiation in mouse hippocampal slices revealed that Myr and RA ameliorated αS synaptic toxicity by inhibition of αS oligomerization. These results suggest that Myr and RA prevent the αS aggregation process, reducing the neurotoxicity of αS oligomers.
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Viorica Raluca Contu Yaichiro Kotake Takashi Toyama Katsuhiro Okuda Masatsugu Miyara Shuichiro Sakamoto Shigeyoshi Samizo Seigo Sanoh Yoshito Kumagai Shigeru Ohta 《Journal of neurochemistry》2014,130(6):826-838
Parkinson's disease (PD) is a common neurodegenerative disease, but its pathogenesis remains elusive. A mutation in ubiquitin C‐terminal hydrolase L1 (UCH‐L1) is responsible for a form of genetic PD which strongly resembles the idiopathic PD. We previously showed that 1‐(3′,4′‐dihydroxybenzyl)‐1,2,3,4‐tetrahydroisoquinoline (3′,4′DHBnTIQ) is an endogenous parkinsonism‐inducing dopamine derivative. Here, we investigated the interaction between 3′,4′DHBnTIQ and UCH‐L1 and its possible role in the pathogenesis of idiopathic PD. Our results indicate that 3′,4′DHBnTIQ binds to UCH‐L1 specifically at Cys152 in vitro. In addition, 3′,4′DHBnTIQ treatment increased the amount of UCH‐L1 in the insoluble fraction of SH‐SY5Y cells and inhibited its hydrolase activity to 60%, reducing the level of ubiquitin in the soluble fraction of SH‐SY5Y cells. Catechol‐modified UCH‐L1 as well as insoluble UCH‐L1 were detected in the midbrain of 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine‐treated PD model mice. Structurally as well as functionally altered UCH‐L1 have been detected in the brains of patients with idiopathic PD. We suggest that conjugation of UCH‐L1 by neurotoxic endogenous compounds such as 3′,4′DHBnTIQ might play a key role in onset and progression of idiopathic PD.
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Cocaine‐ and amphetamine‐regulated transcript peptide in the nucleus accumbens shell inhibits cocaine‐induced locomotor sensitization to transient over‐expression of α‐Ca2+/calmodulin‐dependent protein kinase II 下载免费PDF全文
Lixia Xiong Qing Meng Xi Sun Xiangtong Lu Qiang Fu Qinghua Peng Jianhua Yang Ki‐Wan Oh Zhenzhen Hu 《Journal of neurochemistry》2018,146(3):289-303
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Low levels of methyl β‐cyclodextrin disrupt GluA1‐dependent synaptic potentiation but not synaptic depression 下载免费PDF全文
Tae‐Yong Choi Sunmin Jung Jihoon Nah Hui‐Yeon Ko Su‐Hyun Jo Gehoon Chung Kyungpyo Park Yong‐Keun Jung Se‐Young Choi 《Journal of neurochemistry》2015,132(3):276-285
Methyl‐β‐cyclodextrin (MβCD) is a reagent that depletes cholesterol and disrupts lipid rafts, a type of cholesterol‐enriched cell membrane microdomain. Lipid rafts are essential for neuronal functions such as synaptic transmission and plasticity, which are sensitive to even low doses of MβCD. However, how MβCD changes synaptic function, such as N‐methyl‐d ‐aspartate receptor (NMDA‐R) activity, remains unclear. We monitored changes in synaptic transmission and plasticity after disrupting lipid rafts with MβCD. At low concentrations (0.5 mg/mL), MβCD decreased basal synaptic transmission and miniature excitatory post‐synaptic current without changing NMDA‐R‐mediated synaptic transmission and the paired‐pulse facilitation ratio. Interestingly, low doses of MβCD failed to deplete cholesterol or affect α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor (AMPA‐R) and NMDA‐R levels, while clearly reducing GluA1 levels selectively in the synaptosomal fraction. Low doses of MβCD decreased the inhibitory effects of NASPM, an inhibitor for GluA2‐lacking AMPA‐R. MβCD successfully decreased NMDA‐R‐mediated long‐term potentiation but did not affect the formation of either NMDA‐R‐mediated or group I metabotropic glutamate receptor‐dependent long‐term depression. MβCD inhibited de‐depression without affecting de‐potentiation. These results suggest that MβCD regulates GluA1‐dependent synaptic potentiation but not synaptic depression in a cholesterol‐independent manner.
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Intravenous immunoglobulin (IVIG) contains anti‐amyloid‐β antibodies as well as antibodies providing immunomodulatory effects that may modify chronic inflammation in Alzheimer's disease. Answers to important questions about IVIG transport into the central nervous system and assessments of any impact amyloid‐β has on this transport can be provided by in vitro models of the blood–brain barrier. In this study, amyloid‐β[1‐42] was pre‐aggregated into fibrillar or oligomeric structures, and various concentrations were incubated in the brain side of the blood–brain barrier model, followed by IVIG administration in the blood side at the therapeutically relevant concentrations of 5 and 20 mg/mL. IVIG accumulated in the brain side at physiologically relevant levels, with amyloid‐β pre‐incubation increasing IVIG accumulation. The increased transport effect was dependent on amyloid‐β structural form, amyloid‐β concentration, and IVIG dose. IVIG was found to decrease monocyte chemotactic protein‐1 levels 6.5–18% when low amyloid‐β levels were present and increase levels 4.2–23% when high amyloid‐β levels were present. Therefore, the presence, concentration, and structure of amyloid‐β plays an important role in the effect of IVIG therapy in the brain.
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Allosteric modulation of sigma‐1 receptors by SKF83959 inhibits microglia‐mediated inflammation 下载免费PDF全文
Zhuang Wu Linlang Li Long‐Tai Zheng Zhihong Xu Lin Guo Xuechu Zhen 《Journal of neurochemistry》2015,134(5):904-914
Recent studies have shown that sigma‐1 receptor orthodox agonists can inhibit neuroinflammation. SKF83959 (3‐methyl‐6‐chloro‐7,8‐hydroxy‐1‐[3‐methylphenyl]‐2,3,4,5‐tetrahydro‐1H‐3‐benzazepine), an atypical dopamine receptor‐1 agonist, has been recently identified as a potent allosteric modulator of sigma‐1 receptor. Here, we investigated the anti‐inflammatory effects of SKF83959 in lipopolysaccharide (LPS)‐stimulated BV2 microglia. Our results indicated that SKF83959 significantly suppressed the expression/release of the pro‐inflammatory mediators, such as tumor necrosis factor‐α (TNF‐α), interleukin‐1β (IL‐1β), inducible nitric oxide synthase (iNOS), and inhibited the generation of reactive oxygen species. All of these responses were blocked by selective sigma‐1 receptor antagonists (BD1047 or BD1063) and by ketoconazole (an inhibitor of enzyme cytochrome c17 to inhibit the synthesis of endogenous dehydroepiandrosterone, DHEA). Additionally, we found that SKF83959 promoted the binding activity of DHEA with sigma‐1 receptors, and enhanced the inhibitory effects of DHEA on LPS‐induced microglia activation in a synergic manner. Furthermore, in a microglia‐conditioned media system, SKF83959 inhibited the cytotoxicity of conditioned medium generated by LPS‐activated microglia toward HT‐22 neuroblastoma cells. Taken together, our study provides the first evidence that allosteric modulation of sigma‐1 receptors by SKF83959 inhibits microglia‐mediated inflammation.
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Decreased levels of alpha‐synuclein in cerebrospinal fluid of patients with clinically isolated syndrome and multiple sclerosis 下载免费PDF全文
Roubina Ch. Antonelou Evangelia Emmanouilidou Gerasimos Gasparinatos Theodora Velona Konstantinos I. Voumvourakis Leonidas Stefanis 《Journal of neurochemistry》2015,134(4):748-755
Cerebrospinal fluid (CSF) α‐synuclein (ASYN) levels are emerging as a possible biomarker in a number of neurodegenerative conditions; however, there has been little study of such levels in demyelinating conditions with neurodegeneration such as multiple sclerosis (MS). In this study, we aimed to assess CSF ASYN levels in MS spectrum [clinically isolated syndrome (CIS) and MS] patients and compare them to those obtained in control subjects with benign neurological conditions (BNC). We used a recently developed, ultra‐sensitive sandwich enzyme‐linked immunosorbent assay to measure and compare CSF ASYN levels in three categories of subjects: BNC (n = 38), CIS (n = 36) and MS [Relapsing Remitting (RRMS, n = 22) and Primary Progressive (PPMS, n = 15)]. We also performed secondary analyses, including relationship of CSF ASYN levels to aging, gender, presence of CSF oligoclonal bands (OB) and gadolinium (Gd)‐enhancing demyelinating lesions on T1‐weighted MRIs. CSF ASYN levels were found to be significantly lower in the CIS (78.2 ± 7.5 pg/mL), RRMS (76.8 ± 5.1 pg/mL), and PPMS (76.3 ± 6.7 pg/mL) groups compared to the BNC (125.7 ± 13.6 pg/mL) group. Secondary analyses did not reveal additional correlations. Our results suggest that in a cohort of CIS and MS patients, CSF ASYN levels are decreased, thus providing another possible link between MS and neurodegeneration. Future studies will need to be performed to confirm and extend these findings, to lead to a fuller understanding of the possible biological link between ASYN and MS.