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α-synuclein pathology from the body to the brain:so many seeds so close to the central soil

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Neural Regeneration Research 2024年第7期19卷 1463-1472页

作者： Yunying Yang Zhentao Zhang Department of Neurology Renmin Hospital of Wuhan UniversityWuhanHubei ProvinceChina TaiKang Center for Life and Medical Sciences Wuhan UniversityWuhanHubei ProvinceChina

α-synuclein is a protein that mainly exists in the presynaptic *** folding and accumulation of α-synuclein are found in several neurodegenerative diseases,including Parkinson’s *** and highly phospho rylated a-synuclein constitutes the main component of Lewy bodies in the brain,the pathological hallmark of Parkinson s *** decades,much attention has been focused on the accumulation of α-synuclein in the brain parenchyma rather than considering Parkinson s disease as a systemic *** evidence demonstrates that,at least in some patients,the initial α-synuclein pathology originates in the peripheral organs and spreads to the *** of α-synuclein preformed fibrils into the gastrointestinal tra ct trigge rs the gutto-brain propagation of α-synuclein ***,whether α-synuclein pathology can occur spontaneously in peripheral organs independent of exogenous α-synuclein preformed fibrils or pathological α-synuclein leakage from the central nervous system remains under *** this review,we aimed to summarize the role of peripheral α-synuclein pathology in the pathogenesis of Parkinson’s *** also discuss the pathways by which α-synuclein pathology spreads from the body to the brain.

关键词： aggregation autonomic nervous system barrier receptors body fluid circulation in situ generation Parkinson’s disease phosphorylation propagation synucleinopathies α-synuclein α-synuclein fibrils

α-synuclein-carrying astrocytic extracellular vesicles in Parkinson pathogenesis and diagnosis

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Translational Neurodegeneration 2023年第1期12卷 333-352页

作者： Pan Wang Guoyu Lan Bin Xu Zhenwei Yu Chen Tian Xia Lei Wassilios G.Meissner Tao Feng Ying Yang Jing Zhang Department of Pathology The First Affiliated HospitalZhejiang University School of MedicineHangzhou 310002China National Human Brain Bank for Health and Disease Zhejiang UniversityHangzhou 310002China Department of Pathology Peking University Health Science CenterBeijing 100191China Department of Neurology Center for Movement DisordersBeijing Tiantan HospitalCapital Medical UniversityBeijing 100070China China National Clinical Research Center for Neurological Diseases Beijing 100070China CNRS IMNUMR 5293University of Bordeaux33000 BordeauxFrance CHU Bordeaux Service de Neurologie des Maladies NeurodégénérativesIMNc33000 BordeauxFrance Department of Medicine New Zealand Brain Research InstituteUniversity of OtagoChristchurchChristchurchNew Zealand

Background The accumulation ofα-synuclein(α-syn),an essential step in PD development and progression,is observed not only in neurons but also in glia,including *** mechanisms regulating astrocyticα-syn level and aggregation remain *** recently,it has been demonstrated that a part ofα-syn spreading occurs through extracellular vesicles(EVs),although it is unknown whether this process is involved in astrocytes of *** is known,however,that EVs derived from the central nervous system exist in the blood and are extensively explored as biomarkers for PD and other neurodegenerative *** Primary astrocytes were transfected with A53Tα-syn plasmid or exposed toα-syn *** level of astrocyte-derived EVs(AEVs)was assessed by nanoparticle tracking analysis and *** lysosomal function was evaluated by Cathepsin assays,immunofluorescence for levels of Lamp1 and Lamp2,and LysoTracker Red *** Apogee assays were optimized to measure the GLT-1+AEVs in clinical cohorts of 106 PD,47 multiple system atrophy(MSA),and 103 healthy control(HC)to test the potential of plasma AEVs as a biomarker to differentiate PD from other forms of *** The number of AEVs significantly increased in primary astrocytes withα-syn *** mechanism of increased AEVs was partially attributed to lysosomal *** number ofα-syn-carrying AEVs was significantly higher in patients with PD than in HC and *** integrative model combining AEVs with total and aggregatedα-syn exhibited efficient diagnostic power in differentiating PD from HC with an AUC of 0.915,and from MSA with an AUC of *** Pathologicalα-syn deposition could increase the astrocytic secretion of EVs,possibly throughα-syninduced lysosomal ***α-syn-containing AEVs in the peripheral blood may be an effective biomarker for clinical diagnosis or differential diagnosis of PD.

关键词： Parkinson’s disease Astrocyte Extracellular vesicle α-synuclein Lysosomal dysfunction

α-synuclein conformers reveal link to clinical heterogeneity ofα-synucleinopathies

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Translational Neurodegeneration 2023年第1期12卷 691-701页

作者： Matthias Schmitz NiccolòCandelise Sezgi Canaslan Hermann C.Altmeppen Jakob Matschke Markus Glatzel Neelam Younas Saima Zafar Peter Hermann Inga Zerr Department of Neurology National Reference Center for TSEThe German Center for Neurodegenerative Diseases(DZNE)Georg-August-UniversityUniversity Medicine GottingenGoettingenGermany National Center for Drug Research and Evaluation Institute Superiore di SanitàRomeItaly Institute of Neuropathology University Medical Center Hamburg-Eppendorf(UKE)HamburgGermany

α-synucleinopathies,such as Parkinson’s disease(PD),dementia with Lewy bodies(DLB)and multiple system atrophy,are a class of neurodegenerative diseases exhibiting intracellular inclusions of misfoldedα-synuclein(αSyn),referred to as Lewy bodies or oligodendroglial cytoplasmic inclusions(Papp-Lantos bodies).Even though the specific cellular distribution of aggregatedαSyn differs in PD and DLB patients,both groups show a significant pathological overlap,raising the discussion of whether PD and DLB are the same or different *** clinical investigation,we will focus in addition on methodologies,such as protein seeding assays(real-time quaking-induced conversion),to discriminate between different types ofα-*** approach relies on the seeding conversion properties of misfoldedαSyn,supporting the hypothesis that different conformers of misfoldedαSyn may occur in different types ofα-*** the pathological processes influencing the disease progression and phenotype,provoked by differentαSyn conformers,will be important for a personalized medical treatment in future.

关键词： α-synucleinopathies α-synuclein RT-QuIC Protein strains

α-synuclein arginylation in the human brain

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Translational Neurodegeneration 2022年第1期11卷 654-666页

作者： Jun Zhao Buyan Pan Marie Fina Yun Huang Marie Shimogawa Kelvin C.Luk Elizabeth Rhoades EJames Petersson Dawei W.Dong Anna Kashina Department of Biomedical Sciences University of Pennsylvania School of Veterinary MedicinePhiladelphiaPennsylvania 19104USA Department of Chemistry University of Pennsylvania School of Arts and SciencesPhiladelphiaPennsylvania 19104USA Center for Neurodegenerative Disease Research Department of Pathology and Laboratory MedicineUniversity of Pennsylvania Perelman School of MedicinePhiladelphiaPennsylvania 19104USA.

Background: Alpha-synuclein (α-syn) exhibits pathological misfolding in many human neurodegenerative disorders. We previously showed that α-syn is arginylated in the mouse brain and that lack of arginylation leads to neurodegen-eration in mice. Methods: Here, we tested α-syn arginylation in human brain pathology using newly derived antibodies in combina-tion with Western blotting, biochemical assays, and experiments in live neurons. Results: We found that α-syn was arginylated in the human brain on E46 and E83, two sites previously implicated in α-syn pathology and familial cases of Parkinson’s disease. The levels of arginylation in different brain samples ranged between ~ 3% and ~ 50% of the total α-syn pool, and this arginylation nearly exclusively concentrated in the subcellu-lar α-syn fraction that sedimented at low centrifugation speeds and appeared to be simultaneously targeted by multi-ple posttranslational modifications. Arginylated α-syn was less susceptible to S129 phosphorylation and pathological aggregation in neurons. The arginylation level inversely correlated with the overall α-syn levels and with patient age, suggesting a possible causal relationship between arginylation decline and α-syn-dependent neuropathology. Conclusion: We propose that α-syn arginylation constitutes a potential neuroprotective mechanism that prevents its abnormal accumulation during neurodegeneration and aging in the human brain.

关键词： Arginylation Neurodegeneration Aging α-synuclein

The raphe nuclei are the early lesion site of gastric α-synuclein propagation to the substantia nigra

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Acta Pharmaceutica Sinica B 2024年第5期14卷 2057-2076页

作者： Chenglu Zhang Ruxue Bo Tiantian Zhou Naihong Chen Yuhe Yuan State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Chinese Academy of Medical Sciences&Peking Union Medical College Institute of Materia MedicaBeijing 100050China

Parkinson's disease(PD)is a neurodegeneration disease withα-synuclein accumulated in the substantia nigra pars compacta(SNpc)and most of the dopaminergic neurons are lost in SNpc while patients are diagnosed with *** the pathology at an early stage contributes to the development of the disease-modifying *** the“gut–brain”hypothesis is proposed to explain the underlying mechanism,where the earlier lesioned site in the brain of gastricα-synuclein and howα-synuclein further spreads are not fully *** we report that caudal raphe nuclei(CRN)are the early lesion site of gastricα-synuclein propagating through the spinal cord,while locus coeruleus(LC)and substantia nigra pars compacta(SNpc)were further affected over a time frame of 7 ***α-synuclein propagation via CRN leads to neuron loss and disordered neuron activity,accompanied by abnormal motor and non-motor *** neuron circuits are observed among CRN,LC,and SNpc,which contribute to the venerability of dopaminergic neurons in *** results show that CRN is the key region for the gastricα-synuclein spread to the *** study provides valuable details for the“gut–brain”hypothesis and proposes a valuable PD model for future research on early PD intervention.

关键词： Raphe nuclei α-synuclein Gastrointestinal tract Electrophysiology Locus coeruleus Substantia nigra pars compacta Parkinson's disease Spinal cord

Long-term adenosine A1 receptor activation-induced sortilin expression promotes α-synuclein upregulation in dopaminergic neurons

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Neural Regeneration Research 2020年第4期15卷 712-723页

作者： Yun-Cheng Lv An-Bo Gao Jing Yang Li-Yuan Zhong Bo Jia Shu-Hui Ouyang Le Gui Tian-Hong Peng Sha Sun Francisco S.Cayabyab Clinical Anatomy&Reproductive Medicine Application Institute Hengyang Medical CollegeUniversity of South ChinaHengyangHunan ProvinceChina Department of Surgery College of MedicineUniversity of SaskatchewanSaskatoonCanada Institute of Pharmacy and Pharmacology School of Pharmaceutical ScienceUniversity of South ChinaHengyangHunan ProvinceChina Department of Metabolism&Endocrinology the First Affiliated HospitalHengyang Medical CollegeUniversity of South ChinaHengyangHunan ProvinceChina

Prolonged activation of adenosine A1 receptor likely leads to damage of dopaminergic neurons and subsequent development of neurodegenerative ***,the pathogenesis underlying long-term adenosine A1 receptor activation-induced neurodegeneration remains *** this study,rats were intraperitoneally injected with 5 mg/kg of the adenosine A1 receptor agonist N6-cyclopentyladenosine(CPA)for five *** mobility of rats was evaluated by forced swimming test,while their cognitive capabilities were evaluated by Y-maze *** of sortilin,α-synuclein,p-JUN,and c-JUN proteins in the substantia nigra were detected by western blot *** addition,immunofluorescence staining of sortilin andα-synuclein was performed to detect expression in the substantia *** results showed that,compared with adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine(5 mg/kg)+CPA co-treated rats,motor and memory abilities were reduced,surface expression of sortin andα-synuclein in dopaminergic neurons was reduced,and total sortilin and totalα-synuclein were increased in CPA-treated ***9D cells were incubated with 500 nM CPA alone or in combination with 10μM SP600125(JNK inhibitor)for 48 *** real-time polymerase chain reaction analysis of sortilin andα-synuclein mRNA levels in MN9D cells revealed upregulated sortilin expression in MN9D cells cultured with CPA alone,but the combination of CPA and SP600125 could inhibit this *** made using Jasper,PROMO,and Alibaba online databases identified a highly conserved sequence in the sortilin promoter that was predicted to bind JUN in both humans and rodents.A luciferase reporter assay of sortilin promoter plasmid-transfected HEK293T cells confirmed this *** sortilin expression was inhibited by sh-SORT1,expression of p-JUN and c-JUN was detected by western blot ***-term adenosine A1 receptor activation levels upregulatedα-synuclein expression at the pos

关键词： cognitive dysfunction dopaminergic neuron dyskinesia JNK/c-JUN pathway long-term adenosine A1 receptor activation neural regeneration neurodegenerative diseases sortilin α-synuclein

Revealing the Regulation Effect of Surface Charge at Aromatic Interface to Dynamic Conformational Changes of α-synuclein at Early Aggregation Stage

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Chinese Journal of Chemistry 2024年第16期42卷 1867-1876页

作者： Yuqi Zhang Lie Wu Xiue Jiang State Key Laboratoryof Electroanalytical Chemistry Changchun Institute of Applied ChemistryChinese Academy of SciencesChangchun Jilin 130022China Schoolof Applied Chemistry and Engineering University of Science and Technology of ChinaHefei Anhui 230026China Research Center for Analytical Science College of ChemistryNankai UniversityTianjin 300071China

The aggregation ofα-synuclein(α-syn)is strongly influenced by membrane interfaces,but the mechanism of transition from monomers to oligomers at early aggregation stage is not ***,we investigate the adsorption and structure changes ofα-syn on oppositely charged aromatic interfaces through in-situ surface-enhanced infrared absorption(SEIRA)spectroscopy and nano-IR *** results show that the synergy of electrostatic and hydrophobic interactions leads to a“fast-slow”two-step aggregation pathway on negatively charged *** adsorption induces the formation of an extended helix structure and subsequently partial helix unwinding in NAC region,which enables the hydrophobic stacking between nearby NAC *** antiparallel β-sheet rich aggregates are gradually emerging as further interactions of monomers with the fast formed“first layer”.Monomers electrostatically adsorb on positively charged interface by C-terminus with NAC region and N-terminus stretched in solvent,which serve as an aggregation core and induce further adsorption and gradual formation of aggregates with C-terminus *** results demonstrate the modulation of surface charge and synergy of electrostatic and hydrophobic interactions on the interaction modes and aggregation pathways,which provide insights into dynamic conformation changes ofα-syn at early aggregation stage and imply the important role of spatial-temporal heterogeneity of membranes inα-synucleinopathies.

关键词： α-synuclein Interface Early aggregation IR spectroscopy Surface analysis Analytical methods Proteins Dynamic monitoring

Angiotensin-(1–7)reducesα-synuclein aggregation by enhancing autophagic activity in Parkinson's disease

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Neural Regeneration Research 2022年第5期17卷 1138-1145页

作者： Qing Gao Rui Chen Liang Wu Qing Huang Xi-Xi Wang You-Yong Tian Ying-Dong Zhang Department of Neurology Nanjing First HospitalNanjing Medical UniversityNanjingJiangsu ProvinceChina

Abnormal accumulation ofα-synuclein contributes to the formation of Lewy bodies in the substantia nigra,which is considered the typical pathological hallmark of Parkinson's *** research indicates that angiotensin-(1-7)plays a crucial role in several neurodegenerative disorders,including Parkinson's disease,but the underlying mechanisms remain *** this study,we used intraperitoneal administration of rotenone to male Sprague-Dawley rats for 4 weeks to establish a Parkinson's disease *** investigated whether angiotensin-(1-7)is neuroprotective in this model by continuous administration of angiotensin-(1-7)into the right substantia nigra for 4 *** found that angiotensin-(1-7)infusion relieved characteristic parkinsonian behaviors and reducedα-synuclein aggregation in the substantia *** dopaminergic neurons were extracted from newborn Sprague-Dawley rat substantia nigras and treated with rotenone,angiotensin-(1-7),and/or the Mas receptor blocker A-779 for 24 *** binding to the Mas receptor,angiotensin-(1-7)attenuated apoptosis andα-synuclein aggregation in rotenone-treated *** dopaminergic neurons were also treated with angiotensin-(1-7)and/or the autophagy inhibitor 3-methyladenine for 24 ***-(1-7)increasedα-synuclein removal and increased the autophagy of rotenone-treated *** conclude that angiotensin-(1-7)reducesα-synuclein aggregation by alleviating autophagy dysfunction in Parkinson's ***,the angiotensin-(1-7)/Mas receptor axis plays an important role in the pathogenesis of Parkinson's disease and angiotensin-(1-7)has potential therapeutic value for Parkinson's *** experiments were approved by the Biological Research Ethics Committee of Nanjing First Hospital(approval ***-2000932)in January 2020.

关键词： α-synuclein apoptosis autophagy dopaminergic neuron Lewy bodies neurodegenerative diseases Parkinson's disease renin-angiotensin system rotenone substantia nigra

Cross-talks among GBA mutations,glucocerebrosidase,and a-synuclein in 66/4-associated Parkinson's disease and their targeted therapeutic approaches:a comprehensive review

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Translational Neurodegeneration 2021年第1期10卷 27-39页

作者： Tapan Behl Gagandeep Kaur Ovidiu Fratila Camelia Buhas Claudia Teodora Judea-Pusta Nicoleta Negrut Cristiana Bustea Simona Bungau Chitkara College of Pharmacy Chitkara UniversityRajpuraPunjabIndia Departm ent of Medical Disciplines Faculty of Medicine and PharmacyUniversity of OradeaOradeaRomania Department of Morphological Disciplines Faculty of Medicine and PharmacyUniversity of OradeaOradeaBihor CountyRomania Departm ent of Psycho-Neuroscience and Recovery Faculty of Medicine and PharmacyUniversity of OradeaOradeaRomania Department of Preclinical Disciplines Faculty of Medicine and PharmacyUniversity of OradeaOradeaRomania Department of Pharmacy Faculty of Medicine and PharmacyUniversity of OradeaOradeaRomania

Current therapies for Parkinson's disease(PD)are palliative,of which the levodopa/carbidopa therapy remains the primary choice but is unable to modulate the progression of *** to the complication of such a multifactorial disorder and significant limitations of the therapy,numerous genetic approaches have been proved effective in finding out genes and mechanisms implicated in this *** the observation of a higher frequency of PD in Gaucher's disease(GD),a lysosomal storage condition,mutations of glycosylceramidase beta(GBA)encoding glucocerebrosidase(GCase)have been shown to be involved and have been explored in the context of *** mutations are the most common genetic risk factor of *** studies have revealed the relationships between PD and GM gene mutations,facilitating a better understanding of this *** hypotheses delineate that the pathological mutations of GBA minimize the enzymatic activity of GCase,which affects the proliferation and clearance of α-synuclein;this affects the lysosomal homeostasis,exacerbating the endoplasmic reticulum stress or encouraging the mitochondrial *** of the pathological mechanisms underlying the GM-associated parkinsonism(GBA+PD)advances our understanding of *** review based on current literature aims to elucidate various genetic and clinical characteristics correlated with GBA mutations and to identify the numerous pathological processes underlying GBA+*** also delineate the therapeutic strategies to interfere with the mutant GCase function for further improvement of the related asynuclein-GCase ***,the various therapeutic approaches such as gene therapy,chaperone proteins,and histone deacetylase inhibitors for the treatment of GBA+PD are discussed.

关键词： Parkinson's disease Glycosylceramidase Glucocerebrosidase Gaucher's disease Mutations α-synuclein