Abstract
The abnormal accumulation of α-synuclein in the brain is a common feature of Parkinson’s disease (PD), PD dementia (PDD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA), and synucleinopathies that present with overlapping but distinct clinical symptoms that include motor and cognitive deficits. Synapse degeneration is the crucial neuropathological event in these synucleinopathies and the neuropathological correlate of connectome dysfunction. The cognitive and motor deficits resulting from the connectome dysfunction are currently measured by scalar systems that are limited in their sensitivity and largely subjective. Ideally, a marker of synapse degeneration would correlate with measures of cognitive or motor impairment, and could therefore be used as a more objective, surrogate biomarker of the core clinical features of these diseases. Furthermore, an objective surrogate biomarker that can detect and monitor the progression of synapse degeneration would improve patient management and clinical trial design, and could provide a measure of therapeutic response. Here, we review the published findings relating to candidate biomarkers of synapse degeneration in PD, PDD, DLB, and MSA patient-derived biofluids and discuss the findings in the context of the mechanisms associated with α-synuclein-mediated synapse degeneration. Understanding these mechanisms is essential not only for discovery of biomarkers, but also to improve our understanding of the earliest changes in disease pathogenesis of synucleinopathies.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Availability of data and materials
Not applicable.
References
Abeliovich A, Chen C, Goda Y, Silva AJ, Stevens CF, Tonegawa S (1993) Modified hippocampal long-term potentiation in PKC gamma-mutant mice. Cell 75(7):1253–1262. https://doi.org/10.1016/0092-8674(93)90613-u
Agliardi C, Meloni M, Guerini FR, Zanzottera M, Bolognesi E, Baglio F, Clerici M (2021) Oligomeric alpha-Syn and SNARE complex proteins in peripheral extracellular vesicles of neural origin are biomarkers for Parkinson’s disease. Neurobiol Dis 148:105185. https://doi.org/10.1016/j.nbd.2020.105185
Alpadi K, Kulkarni A, Namjoshi S, Srinivasan S, Sippel KH, Ayscough K, Zieger M, Schmidt A, Mayer A, Evangelista M, Quiocho FA, Peters C (2013) Dynamin-SNARE interactions control trans-SNARE formation in intracellular membrane fusion. Nat Commun 4:1704. https://doi.org/10.1038/ncomms2724
Anantharam A, Axelrod D, Holz RW (2012) Real-time imaging of plasma membrane deformations reveals pre-fusion membrane curvature changes and a role for dynamin in the regulation of fusion pore expansion. J Neurochem 122(4):661–671. https://doi.org/10.1111/j.1471-4159.2012.07816.x
Andersen KB, Hansen AK, Damholdt MF, Horsager J, Skjaerbaek C, Gottrup H, Klit H, Schacht AC, Danielsen EH, Brooks DJ, Borghammer P (2021) Reduced synaptic density in patients with lewy body dementia: an [(11) C]UCB-J PET imaging study. Mov Disord 36(9):2057–2065. https://doi.org/10.1002/mds.28617
Baba M, Nakajo S, Tu PH, Tomita T, Nakaya K, Lee VM, Trojanowski JQ, Iwatsubo T (1998) Aggregation of alpha-synuclein in Lewy bodies of sporadic Parkinson’s disease and dementia with Lewy bodies. Am J Pathol 152(4):879–884
Backstrom DC, Eriksson Domellof M, Linder J, Olsson B, Ohrfelt A, Trupp M, Zetterberg H, Blennow K, Forsgren L (2015) Cerebrospinal fluid patterns and the risk of future dementia in early incident parkinson disease. JAMA Neurol 72(10):1175–1182. https://doi.org/10.1001/jamaneurol.2015.1449
Beach TG, Adler CH, Lue L, Sue LI, Bachalakuri J, Henry-Watson J, Sasse J, Boyer S, Shirohi S, Brooks R, Eschbacher J, White CL 3rd, Akiyama H, Caviness J, Shill HA, Connor DJ, Sabbagh MN, Walker DG (2009) Unified staging system for Lewy body disorders: correlation with nigrostriatal degeneration, cognitive impairment and motor dysfunction. Acta Neuropathol 117(6):613–634. https://doi.org/10.1007/s00401-009-0538-8
Beckmann ND, Lin WJ, Wang M, Cohain AT, Charney AW, Wang P, Ma W, Wang YC, Jiang C, Audrain M, Comella PH, Fakira AK, Hariharan SP, Belbin GM, Girdhar K, Levey AI, Seyfried NT, Dammer EB, Duong D, Lah JJ, Haure-Mirande JV, Shackleton B, Fanutza T, Blitzer R, Kenny E, Zhu J, Haroutunian V, Katsel P, Gandy S, Tu Z, Ehrlich ME, Zhang B, Salton SR, Schadt EE (2020) Multiscale causal networks identify VGF as a key regulator of Alzheimer’s disease. Nat Commun 11(1):3942. https://doi.org/10.1038/s41467-020-17405-z
Bellucci A, Mercuri NB, Venneri A, Faustini G, Longhena F, Pizzi M, Missale C, Spano P (2016) Review: Parkinson’s disease: from synaptic loss to connectome dysfunction. Neuropathol Appl Neurobiol 42(1):77–94. https://doi.org/10.1111/nan.12297
Berardelli A, Wenning GK, Antonini A, Berg D, Bloem BR, Bonifati V, Brooks D, Burn DJ, Colosimo C, Fanciulli A, Ferreira J, Gasser T, Grandas F, Kanovsky P, Kostic V, Kulisevsky J, Oertel W, Poewe W, Reese JP, Relja M, Ruzicka E, Schrag A, Seppi K, Taba P, Vidailhet M (2013) EFNS/MDS-ES/ENS [corrected] recommendations for the diagnosis of Parkinson’s disease. Eur J Neurol 20(1):16–34. https://doi.org/10.1111/ene.12022
Bereczki E, Francis PT, Howlett D, Pereira JB, Hoglund K, Bogstedt A, Cedazo-Minguez A, Baek JH, Hortobagyi T, Attems J, Ballard C, Aarsland D (2016) Synaptic proteins predict cognitive decline in Alzheimer’s disease and Lewy body dementia. Alzheimers Dement 12(11):1149–1158. https://doi.org/10.1016/j.jalz.2016.04.005
Bereczki E, Bogstedt A, Hoglund K, Tsitsi P, Brodin L, Ballard C, Svenningsson P, Aarsland D (2017) Synaptic proteins in CSF relate to Parkinson’s disease stage markers. NPJ Parkinsons Dis 3:7. https://doi.org/10.1038/s41531-017-0008-2
Bereczki E, Branca RM, Francis PT, Pereira JB, Baek JH, Hortobagyi T, Winblad B, Ballard C, Lehtio J, Aarsland D (2018) Synaptic markers of cognitive decline in neurodegenerative diseases: a proteomic approach. Brain 141(2):582–595. https://doi.org/10.1093/brain/awx352
Berglund EO, Murai KK, Fredette B, Sekerkova G, Marturano B, Weber L, Mugnaini E, Ranscht B (1999) Ataxia and abnormal cerebellar microorganization in mice with ablated contactin gene expression. Neuron 24(3):739–750. https://doi.org/10.1016/s0896-6273(00)81126-5
Beyer K, Domingo-Sabat M, Santos C, Tolosa E, Ferrer I, Ariza A (2010) The decrease of beta-synuclein in cortical brain areas defines a molecular subgroup of dementia with Lewy bodies. Brain 133(Pt 12):3724–3733. https://doi.org/10.1093/brain/awq275
Bisaglia M, Bubacco L (2020) Copper ions and parkinson’s disease: why is homeostasis so relevant? Biomolecules. https://doi.org/10.3390/biom10020195
Boiten WA, van Steenoven I, Xiao M, Worley PF, Lemstra AW, Teunissen CE (2020) Pathologically decreased csf levels of synaptic marker NPTX2 in DLB are correlated with levels of alpha-synuclein and VGF. Cells. https://doi.org/10.3390/cells10010038
Bongianni M, Ladogana A, Capaldi S, Klotz S, Baiardi S, Cagnin A, Perra D, Fiorini M, Poleggi A, Legname G, Cattaruzza T, Janes F, Tabaton M, Ghetti B, Monaco S, Kovacs GG, Parchi P, Pocchiari M, Zanusso G (2019) alpha-Synuclein RT-QuIC assay in cerebrospinal fluid of patients with dementia with Lewy bodies. Ann Clin Transl Neurol 6(10):2120–2126. https://doi.org/10.1002/acn3.50897
Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Steur EN, Braak E (2003) Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 24(2):197–211. https://doi.org/10.1016/s0197-4580(02)00065-9
Brockmann K, Quadalti C, Lerche S, Rossi M, Wurster I, Baiardi S, Roeben B, Mammana A, Zimmermann M, Hauser AK, Deuschle C, Schulte C, Waniek K, Lachmann I, Sjodin S, Brinkmalm A, Blennow K, Zetterberg H, Gasser T, Parchi P (2021) Association between CSF alpha-synuclein seeding activity and genetic status in Parkinson’s disease and dementia with Lewy bodies. Acta Neuropathol Commun 9(1):175. https://doi.org/10.1186/s40478-021-01276-6
Broderick PA, Wenning L, Li YS (2017) Neuromolecular imaging, a nanobiotechnology for Parkinson’s disease: advancing pharmacotherapy for personalized medicine. J Neural Transm (vienna) 124(1):57–78. https://doi.org/10.1007/s00702-016-1633-3
Burre J, Sharma M, Tsetsenis T, Buchman V, Etherton MR, Sudhof TC (2010) Alpha-synuclein promotes SNARE-complex assembly in vivo and in vitro. Science 329(5999):1663–1667. https://doi.org/10.1126/science.1195227
Calo L, Wegrzynowicz M, Santivanez-Perez J, Grazia Spillantini M (2016) Synaptic failure and alpha-synuclein. Mov Disord 31(2):169–177. https://doi.org/10.1002/mds.26479
Chatterjee M, Del Campo M, Morrema THJ, de Waal M, van der Flier WM, Hoozemans JJM, Teunissen CE (2018) Contactin-2, a synaptic and axonal protein, is reduced in cerebrospinal fluid and brain tissue in Alzheimer’s disease. Alzheimers Res Ther 10(1):52. https://doi.org/10.1186/s13195-018-0383-x
Chatterjee M, van Steenoven I, Huisman E, Oosterveld L, Berendse H, van der Flier WM, Del Campo M, Lemstra AW, van de Berg WDJ, Teunissen CE (2020) Contactin-1 is reduced in cerebrospinal fluid of Parkinson’s disease patients and is present within lewy bodies. Biomolecules. https://doi.org/10.3390/biom10081177
Cocco C, D’Amato F, Noli B, Ledda A, Brancia C, Bongioanni P, Ferri GL (2010) Distribution of VGF peptides in the human cortex and their selective changes in Parkinson’s and Alzheimer’s diseases. J Anat 217(6):683–693. https://doi.org/10.1111/j.1469-7580.2010.01309.x
Crocker A, Espana RA, Papadopoulou M, Saper CB, Faraco J, Sakurai T, Honda M, Mignot E, Scammell TE (2005) Concomitant loss of dynorphin, NARP, and orexin in narcolepsy. Neurology 65(8):1184–1188. https://doi.org/10.1212/01.wnl.0000168173.71940.ab
De Vos A, Jacobs D, Struyfs H, Fransen E, Andersson K, Portelius E, Andreasson U, De Surgeloose D, Hernalsteen D, Sleegers K, Robberecht C, Van Broeckhoven C, Zetterberg H, Blennow K, Engelborghs S, Vanmechelen E (2015) C-terminal neurogranin is increased in cerebrospinal fluid but unchanged in plasma in Alzheimer’s disease. Alzheimers Dement 11(12):1461–1469. https://doi.org/10.1016/j.jalz.2015.05.012
Dekker LV, De Graan PN, Versteeg DH, Oestreicher AB, Gispen WH (1989) Phosphorylation of B-50 (GAP43) is correlated with neurotransmitter release in rat hippocampal slices. J Neurochem 52(1):24–30. https://doi.org/10.1111/j.1471-4159.1989.tb10893.x
Delva A, Van Weehaeghe D, Koole M, Van Laere K, Vandenberghe W (2020) Loss of presynaptic terminal integrity in the substantia nigra in early Parkinson’s disease. Mov Disord 35(11):1977–1986. https://doi.org/10.1002/mds.28216
Denny JB (2006) Molecular mechanisms, biological actions, and neuropharmacology of the growth-associated protein GAP-43. Curr Neuropharmacol 4(4):293–304. https://doi.org/10.2174/157015906778520782
Dickson DW, Braak H, Duda JE, Duyckaerts C, Gasser T, Halliday GM, Hardy J, Leverenz JB, Del Tredici K, Wszolek ZK, Litvan I (2009) Neuropathological assessment of Parkinson’s disease: refining the diagnostic criteria. Lancet Neurol 8(12):1150–1157. https://doi.org/10.1016/S1474-4422(09)70238-8
Durante V, de Iure A, Loffredo V, Vaikath N, De Risi M, Paciotti S, Quiroga-Varela A, Chiasserini D, Mellone M, Mazzocchetti P, Calabrese V, Campanelli F, Mechelli A, Di Filippo M, Ghiglieri V, Picconi B, El-Agnaf OM, De Leonibus E, Gardoni F, Tozzi A, Calabresi P (2019) Alpha-synuclein targets GluN2A NMDA receptor subunit causing striatal synaptic dysfunction and visuospatial memory alteration. Brain 142(5):1365–1385. https://doi.org/10.1093/brain/awz065
Emre M (2003) Dementia associated with Parkinson’s disease. Lancet Neurol 2(4):229–237. https://doi.org/10.1016/s1474-4422(03)00351-x
Enache D, Pereira JB, Jelic V, Winblad B, Nilsson P, Aarsland D, Bereczki E (2020) Increased cerebrospinal fluid concentration of ZnT3 is associated with cognitive impairment in Alzheimer’s disease. J Alzheimers Dis 77(3):1143–1155. https://doi.org/10.3233/JAD-200498
Eusebi P, Giannandrea D, Biscetti L, Abraha I, Chiasserini D, Orso M, Calabresi P, Parnetti L (2017) Diagnostic utility of cerebrospinal fluid alpha-synuclein in Parkinson’s disease: a systematic review and meta-analysis. Mov Disord 32(10):1389–1400. https://doi.org/10.1002/mds.27110
Fairfoul G, McGuire LI, Pal S, Ironside JW, Neumann J, Christie S, Joachim C, Esiri M, Evetts SG, Rolinski M, Baig F, Ruffmann C, Wade-Martins R, Hu MT, Parkkinen L, Green AJ (2016) Alpha-synuclein RT-QuIC in the CSF of patients with alpha-synucleinopathies. Ann Clin Transl Neurol 3(10):812–818. https://doi.org/10.1002/acn3.338ACN3338
Fernandez A, de Ceballos ML, Rose S, Jenner P, Marsden CD (1996) Alterations in peptide levels in Parkinson’s disease and incidental Lewy body disease. Brain 119(Pt 3):823–830. https://doi.org/10.1093/brain/119.3.823
Friedman LG, Benson DL, Huntley GW (2015) Cadherin-based transsynaptic networks in establishing and modifying neural connectivity. Curr Top Dev Biol 112:415–465. https://doi.org/10.1016/bs.ctdb.2014.11.025
Fu Y, Huang ZJ (2010) Differential dynamics and activity-dependent regulation of alpha- and beta-neurexins at developing GABAergic synapses. Proc Natl Acad Sci USA 107(52):22699–22704. https://doi.org/10.1073/pnas.1011233108
Fusco G, Sanz-Hernandez M, De Simone A (2018) Order and disorder in the physiological membrane binding of alpha-synuclein. Curr Opin Struct Biol 48:49–57. https://doi.org/10.1016/j.sbi.2017.09.004
Gao L, Tang H, Nie K, Wang L, Zhao J, Gan R, Huang J, Zhu R, Feng S, Duan Z, Zhang Y (2015) Cerebrospinal fluid alpha-synuclein as a biomarker for Parkinson’s disease diagnosis: a systematic review and meta-analysis. Int J Neurosci 125(9):645–654. https://doi.org/10.3109/00207454.2014.961454
Garcia-Reitbock P, Anichtchik O, Bellucci A, Iovino M, Ballini C, Fineberg E, Ghetti B, Della Corte L, Spano P, Tofaris GK, Goedert M, Spillantini MG (2010) SNARE protein redistribution and synaptic failure in a transgenic mouse model of Parkinson’s disease. Brain 133(Pt 7):2032–2044. https://doi.org/10.1093/brain/awq132
Gelb DJ, Oliver E, Gilman S (1999) Diagnostic criteria for Parkinson disease. Arch Neurol 56(1):33–39. https://doi.org/10.1001/archneur.56.1.33
George S, Rey NL, Tyson T, Esquibel C, Meyerdirk L, Schulz E, Pierce S, Burmeister AR, Madaj Z, Steiner JA, Escobar Galvis ML, Brundin L, Brundin P (2019) Microglia affect alpha-synuclein cell-to-cell transfer in a mouse model of Parkinson’s disease. Mol Neurodegener 14(1):34. https://doi.org/10.1186/s13024-019-0335-3
Geser F, Wenning GK, Poewe W, McKeith I (2005) How to diagnose dementia with Lewy bodies: state of the art. Mov Disord 20(Suppl 12):S11-20. https://doi.org/10.1002/mds.20535
Gilman S, Low P, Quinn N, Albanese A, Ben-Shlomo Y, Fowler C, Kaufmann H, Klockgether T, Lang A, Lantos P, Litvan I, Mathias C, Oliver E, Robertson D, Schatz I, Wenning G (1998) Consensus statement on the diagnosis of multiple system atrophy. American Autonomic Society and American Academy of Neurology. Clin Auton Res 8(6):359–362. https://doi.org/10.1007/BF02309628
Gilman S, Wenning GK, Low PA, Brooks DJ, Mathias CJ, Trojanowski JQ, Wood NW, Colosimo C, Durr A, Fowler CJ, Kaufmann H, Klockgether T, Lees A, Poewe W, Quinn N, Revesz T, Robertson D, Sandroni P, Seppi K, Vidailhet M (2008) Second consensus statement on the diagnosis of multiple system atrophy. Neurology 71(9):670–676. https://doi.org/10.1212/01.wnl.0000324625.00404.15
Gonzalo S, Linder ME (1998) SNAP-25 palmitoylation and plasma membrane targeting require a functional secretory pathway. Mol Biol Cell 9(3):585–597. https://doi.org/10.1091/mbc.9.3.585
Halbgebauer S, Oeckl P, Steinacker P, Yilmazer-Hanke D, Anderl-Straub S, von Arnim C, Froelich L, Gomes LA, Hausner L, Huss A, Jahn H, Weishaupt J, Ludolph AC, Thal DR, Otto M (2020) Beta-synuclein in cerebrospinal fluid as an early diagnostic marker of Alzheimer’s disease. J Neurol Neurosurg Psychiatry. https://doi.org/10.1136/jnnp-2020-324306
Hall S, Janelidze S, Zetterberg H, Brix B, Mattsson N, Surova Y, Blennow K, Hansson O (2020) Cerebrospinal fluid levels of neurogranin in Parkinsonian disorders. Mov Disord 35(3):513–518. https://doi.org/10.1002/mds.27950
Hashimoto M, Rockenstein E, Mante M, Mallory M, Masliah E (2001) beta-Synuclein inhibits alpha-synuclein aggregation: a possible role as an anti-parkinsonian factor. Neuron 32(2):213–223. https://doi.org/10.1016/s0896-6273(01)00462-7
He Q, Dent EW, Meiri KF (1997) Modulation of actin filament behavior by GAP-43 (neuromodulin) is dependent on the phosphorylation status of serine 41, the protein kinase C site. J Neurosci 17(10):3515–3524
Heinzel S, Berg D, Gasser T, Chen H, Yao C, Postuma RB (2019) Update of the MDS research criteria for prodromal Parkinson’s disease. Mov Disord 34(10):1464–1470. https://doi.org/10.1002/mds.27802
Hoffmann A, Ettle B, Bruno A, Kulinich A, Hoffmann AC, von Wittgenstein J, Winkler J, Xiang W, Schlachetzki JCM (2016) Alpha-synuclein activates BV2 microglia dependent on its aggregation state. Biochem Biophys Res Commun 479(4):881–886. https://doi.org/10.1016/j.bbrc.2016.09.109
Holahan MR (2017) A shift from a pivotal to supporting role for the growth-associated protein (GAP-43) in the coordination of axonal structural and functional plasticity. Front Cell Neurosci 11:266. https://doi.org/10.3389/fncel.2017.00266
Hughes AJ, Daniel SE, Kilford L, Lees AJ (1992) Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry 55(3):181–184. https://doi.org/10.1136/jnnp.55.3.181
Hyman BT, Phelps CH, Beach TG, Bigio EH, Cairns NJ, Carrillo MC, Dickson DW, Duyckaerts C, Frosch MP, Masliah E, Mirra SS, Nelson PT, Schneider JA, Thal DR, Thies B, Trojanowski JQ, Vinters HV, Montine TJ (2012) National institute on aging-Alzheimer’s association guidelines for the neuropathologic assessment of Alzheimer’s disease. Alzheimers Dement 8(1):1–13. https://doi.org/10.1016/j.jalz.2011.10.007
Iwai N, Shimoike H, Ohmichi N, Kinoshita M (1995) Angiotensinogen gene and blood pressure in the Japanese population. Hypertension 25(4 Pt 2):688–693
Janelidze S, Hertze J, Zetterberg H, Landqvist Waldo M, Santillo A, Blennow K, Hansson O (2016) Cerebrospinal fluid neurogranin and YKL-40 as biomarkers of Alzheimer’s disease. Ann Clin Transl Neurol 3(1):12–20. https://doi.org/10.1002/acn3.266ACN3266
Jeannotte AM, Sidhu A (2008) Regulated interactions of the norepineprhine transporter by the actin and microtubule cytoskeletons. J Neurochem 105(5):1668–1682. https://doi.org/10.1111/j.1471-4159.2008.05258.x
Jellinger KA (2003) Neuropathological spectrum of synucleinopathies. Mov Disord 18(Suppl 6):S2-12. https://doi.org/10.1002/mds.10557
Khundakar AA, Hanson PS, Erskine D, Lax NZ, Roscamp J, Karyka E, Tsefou E, Singh P, Cockell SJ, Gribben A, Ramsay L, Blain PG, Mosimann UP, Lett DJ, Elstner M, Turnbull DM, Xiang CC, Brownstein MJ, O’Brien JT, Taylor JP, Attems J, Thomas AJ, McKeith IG, Morris CM (2016) Analysis of primary visual cortex in dementia with Lewy bodies indicates GABAergic involvement associated with recurrent complex visual hallucinations. Acta Neuropathol Commun 4(1):66. https://doi.org/10.1186/s40478-016-0334-3
Kirkpatrick LL, Matzuk MM, Dodds DC, Perin MS (2000) Biochemical interactions of the neuronal pentraxins. Neuronal pentraxin (NP) receptor binds to taipoxin and taipoxin-associated calcium-binding protein 49 via NP1 and NP2. J Biol Chem 275(23):17786–17792. https://doi.org/10.1074/jbc.M002254200
Koob AO, Shaked GM, Bender A, Bisquertt A, Rockenstein E, Masliah E (2014) Neurogranin binds alpha-synuclein in the human superior temporal cortex and interaction is decreased in Parkinson’s disease. Brain Res 1591:102–110. https://doi.org/10.1016/j.brainres.2014.10.013
Koopmans F, van Nierop P, Andres-Alonso M, Byrnes A, Cijsouw T, Coba MP, Cornelisse LN, Farrell RJ, Goldschmidt HL, Howrigan DP, Hussain NK, Imig C, de Jong APH, Jung H, Kohansalnodehi M, Kramarz B, Lipstein N, Lovering RC, MacGillavry H, Mariano V, Mi H, Ninov M, Osumi-Sutherland D, Pielot R, Smalla KH, Tang H, Tashman K, Toonen RFG, Verpelli C, Reig-Viader R, Watanabe K, van Weering J, Achsel T, Ashrafi G, Asi N, Brown TC, De Camilli P, Feuermann M, Foulger RE, Gaudet P, Joglekar A, Kanellopoulos A, Malenka R, Nicoll RA, Pulido C, de Juan-Sanz J, Sheng M, Sudhof TC, Tilgner HU, Bagni C, Bayes A, Biederer T, Brose N, Chua JJE, Dieterich DC, Gundelfinger ED, Hoogenraad C, Huganir RL, Jahn R, Kaeser PS, Kim E, Kreutz MR, McPherson PS, Neale BM, O’Connor V, Posthuma D, Ryan TA, Sala C, Feng G, Hyman SE, Thomas PD, Smit AB, Verhage M (2019) SynGO: an evidence-based, expert-curated knowledge base for the synapse. Neuron 103(2):217–234. https://doi.org/10.1016/j.neuron.2019.05.002
Lautenschlager J, Stephens AD, Fusco G, Strohl F, Curry N, Zacharopoulou M, Michel CH, Laine R, Nespovitaya N, Fantham M, Pinotsi D, Zago W, Fraser P, Tandon A, St George-Hyslop P, Rees E, Phillips JJ, De Simone A, Kaminski CF, Schierle GSK (2018) C-terminal calcium binding of alpha-synuclein modulates synaptic vesicle interaction. Nat Commun 9(1):712. https://doi.org/10.1038/s41467-018-03111-4
Lee JY, Kim JS, Byun HR, Palmiter RD, Koh JY (2011) Dependence of the histofluorescently reactive zinc pool on zinc transporter-3 in the normal brain. Brain Res 1418:12–22. https://doi.org/10.1016/j.brainres.2011.08.055
Lee SJ, Wei M, Zhang C, Maxeiner S, Pak C, Calado Botelho S, Trotter J, Sterky FH, Sudhof TC (2017) Presynaptic neuronal pentraxin receptor organizes excitatory and inhibitory synapses. J Neurosci 37(5):1062–1080. https://doi.org/10.1523/JNEUROSCI.2768-16.2016
Lopantsev V, Wenzel HJ, Cole TB, Palmiter RD, Schwartzkroin PA (2003) Lack of vesicular zinc in mossy fibers does not affect synaptic excitability of CA3 pyramidal cells in zinc transporter 3 knockout mice. Neuroscience 116(1):237–248. https://doi.org/10.1016/s0306-4522(02)00570-5
Lou X, Kim J, Hawk BJ, Shin YK (2017) alpha-Synuclein may cross-bridge v-SNARE and acidic phospholipids to facilitate SNARE-dependent vesicle docking. Biochem J 474(12):2039–2049. https://doi.org/10.1042/BCJ20170200
Lowther ER, O’Brien JT, Firbank MJ, Blamire AM (2014) Lewy body compared with Alzheimer dementia is associated with decreased functional connectivity in resting state networks. Psychiatry Res 223(3):192–201. https://doi.org/10.1016/j.pscychresns.2014.06.004
Luo C, Chen Q, Song W, Chen K, Guo X, Yang J, Huang X, Gong Q, Shang HF (2014) Resting-state fMRI study on drug-naive patients with Parkinson’s disease and with depression. J Neurol Neurosurg Psychiatry 85(6):675–683. https://doi.org/10.1136/jnnp-2013-306237
Magdalinou NK, Paterson RW, Schott JM, Fox NC, Mummery C, Blennow K, Bhatia K, Morris HR, Giunti P, Warner TT, de Silva R, Lees AJ, Zetterberg H (2015) A panel of nine cerebrospinal fluid biomarkers may identify patients with atypical parkinsonian syndromes. J Neurol Neurosurg Psychiatry 86(11):1240–1247. https://doi.org/10.1136/jnnp-2014-309562
Mahul-Mellier A-L, Burtscher J, Maharjan N, Weerens L, Croisier M, Kuttler F, Leleu M, Knott GW, Lashuel HA (2020) The process of Lewy body formation, rather than simply α-synuclein fibrillization, is one of the major drivers of neurodegeneration. Proc Natl Acad Sci 117(9):4971–4982. https://doi.org/10.1073/pnas.1913904117
Maroteaux L, Campanelli JT, Scheller RH (1988) Synuclein: a neuron-specific protein localized to the nucleus and presynaptic nerve terminal. J Neurosci 8(8):2804–2815
Matuskey D, Tinaz S, Wilcox KC, Naganawa M, Toyonaga T, Dias M, Henry S, Pittman B, Ropchan J, Nabulsi N, Suridjan I, Comley RA, Huang Y, Finnema SJ, Carson RE (2020) Synaptic changes in parkinson disease assessed with in vivo imaging. Ann Neurol 87(3):329–338. https://doi.org/10.1002/ana.25682
McCormack A, Keating DJ, Chegeni N, Colella A, Wang JJ, Chataway T (2019) Abundance of synaptic vesicle-related proteins in alpha-synuclein-containing protein inclusions suggests a targeted formation mechanism. Neurotox Res 35(4):883–897. https://doi.org/10.1007/s12640-019-00014-0
McKeith IG, Galasko D, Kosaka K (1996) Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): Report of the consortium on DLB international workshop. Neurology 47:1113–1124
McKeith IG, Dickson DW, Lowe J, Emre M, O’Brien JT, Feldman H, Cummings J, Duda JE, Lippa C, Perry EK, Aarsland D, Arai H, Ballard CG, Boeve B, Burn DJ, Costa D, Del Ser T, Dubois B, Galasko D, Gauthier S, Goetz CG, Gomez-Tortosa E, Halliday G, Hansen LA, Hardy J, Iwatsubo T, Kalaria RN, Kaufer D, Kenny RA, Korczyn A, Kosaka K, Lee VM, Lees A, Litvan I, Londos E, Lopez OL, Minoshima S, Mizuno Y, Molina JA, Mukaetova-Ladinska EB, Pasquier F, Perry RH, Schulz JB, Trojanowski JQ, Yamada M, Consortium on DLB (2005) Diagnosis and management of dementia with Lewy bodies: third report of the DLB consortium. Neurology 65(12):1863–1872. https://doi.org/10.1212/01.wnl.0000187889.17253.b1
McKeith IG, Boeve BF, Dickson DW, Halliday G, Taylor JP, Weintraub D, Aarsland D, Galvin J, Attems J, Ballard CG, Bayston A, Beach TG, Blanc F, Bohnen N, Bonanni L, Bras J, Brundin P, Burn D, Chen-Plotkin A, Duda JE, El-Agnaf O, Feldman H, Ferman TJ, Ffytche D, Fujishiro H, Galasko D, Goldman JG, Gomperts SN, Graff-Radford NR, Honig LS, Iranzo A, Kantarci K, Kaufer D, Kukull W, Lee VMY, Leverenz JB, Lewis S, Lippa C, Lunde A, Masellis M, Masliah E, McLean P, Mollenhauer B, Montine TJ, Moreno E, Mori E, Murray M, O’Brien JT, Orimo S, Postuma RB, Ramaswamy S, Ross OA, Salmon DP, Singleton A, Taylor A, Thomas A, Tiraboschi P, Toledo JB, Trojanowski JQ, Tsuang D, Walker Z, Yamada M, Kosaka K (2017) Diagnosis and management of dementia with Lewy bodies: fourth consensus report of the DLB consortium. Neurology 89(1):88–100. https://doi.org/10.1212/WNL.0000000000004058
McKeith IG, Ferman TJ, Thomas AJ, Blanc F, Boeve BF, Fujishiro H, Kantarci K, Muscio C, O’Brien JT, Postuma RB, Aarsland D, Ballard C, Bonanni L, Donaghy P, Emre M, Galvin JE, Galasko D, Goldman JG, Gomperts SN, Honig LS, Ikeda M, Leverenz JB, Lewis SJG, Marder KS, Masellis M, Salmon DP, Taylor JP, Tsuang DW, Walker Z, Tiraboschi P (2020) Research criteria for the diagnosis of prodromal dementia with Lewy bodies. Neurology 94(17):743–755. https://doi.org/10.1212/WNL.0000000000009323
Miki Y, Foti SC, Asi YT, Tsushima E, Quinn N, Ling H, Holton JL (2019) Improving diagnostic accuracy of multiple system atrophy: a clinicopathological study. Brain 142(9):2813–2827. https://doi.org/10.1093/brain/awz189
Mollenhauer B, Zimmermann J, Sixel-Doring F, Focke NK, Wicke T, Ebentheuer J, Schaumburg M, Lang E, Trautmann E, Zetterberg H, Taylor P, Friede T, Trenkwalder C (2016) Monitoring of 30 marker candidates in early Parkinson disease as progression markers. Neurology 87(2):168–177. https://doi.org/10.1212/WNL.0000000000002651
Mollenhauer B, Caspell-Garcia CJ, Coffey CS, Taylor P, Shaw LM, Trojanowski JQ, Singleton A, Frasier M, Marek K, Galasko D (2017) Longitudinal CSF biomarkers in patients with early Parkinson disease and healthy controls. Neurology 89(19):1959–1969. https://doi.org/10.1212/WNL.0000000000004609
Moran LB, Hickey L, Michael GJ, Derkacs M, Christian LM, Kalaitzakis ME, Pearce RK, Graeber MB (2008) Neuronal pentraxin II is highly upregulated in Parkinson’s disease and a novel component of Lewy bodies. Acta Neuropathol 115(4):471–478. https://doi.org/10.1007/s00401-007-0309-3
Nemani VM, Lu W, Berge V, Nakamura K, Onoa B, Lee MK, Chaudhry FA, Nicoll RA, Edwards RH (2010) Increased expression of alpha-synuclein reduces neurotransmitter release by inhibiting synaptic vesicle reclustering after endocytosis. Neuron 65(1):66–79. https://doi.org/10.1016/j.neuron.2009.12.023
Nicastro N, Holland N, Savulich G, Carter SF, Mak E, Hong YT, Milicevic Sephton S, Fryer TD, Aigbirhio FI, Rowe JB, O’Brien JT (2020) (11)C-UCB-J synaptic PET and multimodal imaging in dementia with Lewy bodies. Eur J Hybrid Imaging 4(1):25. https://doi.org/10.1186/s41824-020-00093-9
Ninkina N, Millership SJ, Peters OM, Connor-Robson N, Chaprov K, Kopylov AT, Montoya A, Kramer H, Withers DJ, Buchman VL (2021) beta-synuclein potentiates synaptic vesicle dopamine uptake and rescues dopaminergic neurons from MPTP-induced death in the absence of other synucleins. J Biol Chem 297(6):101375. https://doi.org/10.1016/j.jbc.2021.101375
O’Brien RJ, Xu D, Petralia RS, Steward O, Huganir RL, Worley P (1999) Synaptic clustering of AMPA receptors by the extracellular immediate-early gene product Narp. Neuron 23(2):309–323. https://doi.org/10.1016/s0896-6273(00)80782-5
Oeckl P, Metzger F, Nagl M, von Arnim CA, Halbgebauer S, Steinacker P, Ludolph AC, Otto M (2016) Alpha-, beta-, and gamma-synuclein quantification in cerebrospinal fluid by multiple reaction monitoring reveals increased concentrations in alzheimer’s and creutzfeldt-jakob disease but no alteration in synucleinopathies. Mol Cell Proteom 15(10):3126–3138. https://doi.org/10.1074/mcp.M116.059915
Oeckl P, Halbgebauer S, Anderl-Straub S, von Arnim CAF, Diehl-Schmid J, Froelich L, Grimmer T, Hausner L, Denk J, Jahn H, Steinacker P, Weishaupt JH, Ludolph AC, Otto M (2020) Targeted mass spectrometry suggests beta-synuclein as synaptic blood marker in alzheimer’s disease. J Proteome Res 19(3):1310–1318. https://doi.org/10.1021/acs.jproteome.9b00824
Olanow CW, Savolainen M, Chu Y, Halliday GM, Kordower JH (2019) Temporal evolution of microglia and alpha-synuclein accumulation following foetal grafting in Parkinson’s disease. Brain 142(6):1690–1700. https://doi.org/10.1093/brain/awz104
Paik SR, Shin HJ, Lee JH, Chang CS, Kim J (1999) Copper(II)-induced self-oligomerization of alpha-synuclein. Biochem J 340(Pt 3):821–828
Palmiter RD, Cole TB, Quaife CJ, Findley SD (1996) ZnT-3, a putative transporter of zinc into synaptic vesicles. Proc Natl Acad Sci USA 93(25):14934–14939. https://doi.org/10.1073/pnas.93.25.14934
Paoletti P, Ascher P, Neyton J (1997) High-affinity zinc inhibition of NMDA NR1-NR2A receptors. J Neurosci 17(15):5711–5725
Parnetti L, Farotti L, Eusebi P, Chiasserini D, De Carlo C, Giannandrea D, Salvadori N, Lisetti V, Tambasco N, Rossi A, Majbour NK, El-Agnaf O, Calabresi P (2014) Differential role of CSF alpha-synuclein species, tau, and Abeta42 in Parkinson’s Disease. Front Aging Neurosci 6:53. https://doi.org/10.3389/fnagi.2014.00053
Peraza LR, Kaiser M, Firbank M, Graziadio S, Bonanni L, Onofrj M, Colloby SJ, Blamire A, O’Brien J, Taylor JP (2014) fMRI resting state networks and their association with cognitive fluctuations in dementia with Lewy bodies. Neuroimage Clin 4:558–565. https://doi.org/10.1016/j.nicl.2014.03.013
Pierre K, Dupouy B, Allard M, Poulain DA, Theodosis DT (2001) Mobilization of the cell adhesion glycoprotein F3/contactin to axonal surfaces is activity dependent. Eur J Neurosci 14(4):645–656. https://doi.org/10.1046/j.0953-816x.2001.01682.x
Pissadaki EK, Bolam JP (2013) The energy cost of action potential propagation in dopamine neurons: clues to susceptibility in Parkinson’s disease. Front Comput Neurosci 7:13. https://doi.org/10.3389/fncom.2013.00013
Poggiolini I, Gupta V, Lawton M, Lee S, El-Turabi A, Querejeta-Coma A, Trenkwalder C, Sixel-Doring F, Foubert-Samier A, Le Traon AP, Plazzi G, Biscarini F, Montplaisir J, Gagnon JF, Postuma RB, Antelmi E, Meissner WG, Mollenhauer B, Ben-Shlomo Y, Hu MT, Parkkinen L (2021) Diagnostic value of cerebrospinal fluid alpha-synuclein seed quantification in synucleinopathies. Brain. https://doi.org/10.1093/brain/awab431
Portelius E, Olsson B, Hoglund K, Cullen NC, Kvartsberg H, Andreasson U, Zetterberg H, Sandelius A, Shaw LM, Lee VMY, Irwin DJ, Grossman M, Weintraub D, Chen-Plotkin A, Wolk DA, McCluskey L, Elman L, McBride J, Toledo JB, Trojanowski JQ, Blennow K (2018) Cerebrospinal fluid neurogranin concentration in neurodegeneration: relation to clinical phenotypes and neuropathology. Acta Neuropathol 136(3):363–376. https://doi.org/10.1007/s00401-018-1851-x
Postuma RB, Berg D, Stern M, Poewe W, Olanow CW, Oertel W, Obeso J, Marek K, Litvan I, Lang AE, Halliday G, Goetz CG, Gasser T, Dubois B, Chan P, Bloem BR, Adler CH, Deuschl G (2015) MDS clinical diagnostic criteria for Parkinson’s disease. Mov Disord 30(12):1591–1601. https://doi.org/10.1002/mds.26424
Prots I, Grosch J, Brazdis RM, Simmnacher K, Veber V, Havlicek S, Hannappel C, Krach F, Krumbiegel M, Schutz O, Reis A, Wrasidlo W, Galasko DR, Groemer TW, Masliah E, Schlotzer-Schrehardt U, Xiang W, Winkler J, Winner B (2018) alpha-Synuclein oligomers induce early axonal dysfunction in human iPSC-based models of synucleinopathies. Proc Natl Acad Sci USA 115(30):7813–7818. https://doi.org/10.1073/pnas.1713129115
Puzzo D, Bizzoca A, Privitera L, Furnari D, Giunta S, Girolamo F, Pinto M, Gennarini G, Palmeri A (2013) F3/Contactin promotes hippocampal neurogenesis, synaptic plasticity, and memory in adult mice. Hippocampus 23(12):1367–1382. https://doi.org/10.1002/hipo.22186
Quadalti C, Calandra-Buonaura G, Baiardi S, Mastrangelo A, Rossi M, Zenesini C, Giannini G, Candelise N, Sambati L, Polischi B, Plazzi G, Capellari S, Cortelli P, Parchi P (2021) Neurofilament light chain and alpha-synuclein RT-QuIC as differential diagnostic biomarkers in parkinsonisms and related syndromes. NPJ Parkinsons Dis 7(1):93. https://doi.org/10.1038/s41531-021-00232-4
Remnestal J, Just D, Mitsios N, Fredolini C, Mulder J, Schwenk JM, Uhlen M, Kultima K, Ingelsson M, Kilander L, Lannfelt L, Svenningsson P, Nellgard B, Zetterberg H, Blennow K, Nilsson P, Haggmark-Manberg A (2016) CSF profiling of the human brain enriched proteome reveals associations of neuromodulin and neurogranin to Alzheimer’s disease. Proteomics Clin Appl 10(12):1242–1253. https://doi.org/10.1002/prca.201500150
Rossi M, Baiardi S, Teunissen CE, Quadalti C, van de Beek M, Mammana A, Stanzani-Maserati M, Van der Flier WM, Sambati L, Zenesini C, Caughey B, Capellari S, Lemstra AW, Parchi P (2021) Diagnostic value of the CSF alpha-synuclein real-time quaking-induced conversion assay at the prodromal MCI stage of dementia with lewy bodies. Neurology 97(9):e930–e940. https://doi.org/10.1212/WNL.0000000000012438
Rudenko G (2017) Dynamic control of synaptic adhesion and organizing molecules in synaptic plasticity. Neural Plast 2017:6526151. https://doi.org/10.1155/2017/6526151
Ruiz A, Walker MC, Fabian-Fine R, Kullmann DM (2004) Endogenous zinc inhibits GABA(A) receptors in a hippocampal pathway. J Neurophysiol 91(2):1091–1096. https://doi.org/10.1152/jn.00755.2003
Rust MB, Maritzen T (2015) Relevance of presynaptic actin dynamics for synapse function and mouse behavior. Exp Cell Res 335(2):165–171. https://doi.org/10.1016/j.yexcr.2014.12.020
Sako W, Murakami N, Izumi Y, Kaji R (2014) Reduced alpha-synuclein in cerebrospinal fluid in synucleinopathies: evidence from a meta-analysis. Mov Disord 29(13):1599–1605. https://doi.org/10.1002/mds.26036
Sandelius A, Portelius E, Kallen A, Zetterberg H, Rot U, Olsson B, Toledo JB, Shaw LM, Lee VMY, Irwin DJ, Grossman M, Weintraub D, Chen-Plotkin A, Wolk DA, McCluskey L, Elman L, Kostanjevecki V, Vandijck M, McBride J, Trojanowski JQ, Blennow K (2019) Elevated CSF GAP-43 is Alzheimer’s disease specific and associated with tau and amyloid pathology. Alzheimers Dement 15(1):55–64. https://doi.org/10.1016/j.jalz.2018.08.006
Sauvola CW, Littleton JT (2021) SNARE regulatory proteins in synaptic vesicle fusion and recycling. Front Mol Neurosci 14:733138. https://doi.org/10.3389/fnmol.2021.733138
Selnes P, Stav AL, Johansen KK, Bjornerud A, Coello C, Auning E, Kalheim L, Almdahl IS, Hessen E, Zetterberg H, Blennow K, Aarsland D, Fladby T (2017) Impaired synaptic function is linked to cognition in Parkinson’s disease. Ann Clin Transl Neurol 4(10):700–713. https://doi.org/10.1002/acn3.446
Sensi SL, Paoletti P, Bush AI, Sekler I (2009) Zinc in the physiology and pathology of the CNS. Nat Rev Neurosci 10(11):780–791. https://doi.org/10.1038/nrn2734
Sevlever D, Zou F, Ma L, Carrasquillo S, Crump MG, Culley OJ, Hunter TA, Bisceglio GD, Younkin L, Allen M, Carrasquillo MM, Sando SB, Aasly JO, Dickson DW, Graff-Radford NR, Petersen RC, Deak F, Belbin O (2015) Genetically-controlled vesicle-associated membrane protein 1 expression may contribute to Alzheimer’s pathophysiology and susceptibility. Mol Neurodegener 10:18. https://doi.org/10.1186/s13024-015-0015-x
Shahnawaz M, Tokuda T, Waragai M, Mendez N, Ishii R, Trenkwalder C, Mollenhauer B, Soto C (2017) Development of a biochemical diagnosis of Parkinson disease by detection of alpha-synuclein misfolded aggregates in cerebrospinal fluid. JAMA Neurol 74(2):163–172. https://doi.org/10.1001/jamaneurol.2016.4547
Sikora J, Ouagazzal AM (2021) Synaptic zinc: an emerging player in Parkinson’s disease. Int J Mol Sci. https://doi.org/10.3390/ijms22094724
Singer W, Schmeichel AM, Shahnawaz M, Schmelzer JD, Boeve BF, Sletten DM, Gehrking TL, Gehrking JA, Olson AD, Savica R, Suarez MD, Soto C, Low PA (2020) Alpha-synuclein oligomers and neurofilament light chain in spinal fluid differentiate multiple system atrophy from lewy body synucleinopathies. Ann Neurol 88(3):503–512. https://doi.org/10.1002/ana.25824
Sjogren M, Minthon L, Davidsson P, Granerus AK, Clarberg A, Vanderstichele H, Vanmechelen E, Wallin A, Blennow K (2000) CSF levels of tau, beta-amyloid(1–42) and GAP-43 in frontotemporal dementia, other types of dementia and normal aging. J Neural Transm (vienna) 107(5):563–579. https://doi.org/10.1007/s007020070079
Soldan A, Moghekar A, Walker KA, Pettigrew C, Hou X, Lu H, Miller MI, Alfini A, Albert M, Xu D, Xiao MF, Worley P (2019) Resting-state functional connectivity is associated with cerebrospinal fluid levels of the synaptic protein NPTX2 in non-demented older adults. Front Aging Neurosci 11:132. https://doi.org/10.3389/fnagi.2019.00132
Sorrentino ZA, Giasson BI, Chakrabarty P (2019) alpha-Synuclein and astrocytes: tracing the pathways from homeostasis to neurodegeneration in Lewy body disease. Acta Neuropathol 138(1):1–21. https://doi.org/10.1007/s00401-019-01977-2
Sourty M, Thoraval L, Roquet D, Armspach JP, Foucher J, Blanc F (2016) Identifying dynamic functional connectivity changes in dementia with lewy bodies based on product hidden Markov models. Front Comput Neurosci 10:60. https://doi.org/10.3389/fncom.2016.00060
Sousa VL, Bellani S, Giannandrea M, Yousuf M, Valtorta F, Meldolesi J, Chieregatti E (2009) α-synuclein and its A30P mutant affect actin cytoskeletal structure and dynamics. Mol Biol Cell 20(16):3725–3739. https://doi.org/10.1091/mbc.e08-03-0302
Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M (1997) Alpha-synuclein in Lewy bodies. Nature 388(6645):839–840. https://doi.org/10.1038/42166
Stoeckli ET (2010) Neural circuit formation in the cerebellum is controlled by cell adhesion molecules of the Contactin family. Cell Adh Migr 4(4):523–526. https://doi.org/10.4161/cam.4.4.12733
Taguchi K, Watanabe Y, Tsujimura A, Tanaka M (2016) Brain region-dependent differential expression of alpha-synuclein. J Comp Neurol 524(6):1236–1258. https://doi.org/10.1002/cne.23901
Tai CY, Mysore SP, Chiu C, Schuman EM (2007) Activity-regulated N-cadherin endocytosis. Neuron 54(5):771–785. https://doi.org/10.1016/j.neuron.2007.05.013
Trojanowski JQ, Revesz T (2007) Proposed neuropathological criteria for the post mortem diagnosis of multiple system atrophy. Neuropathol Appl Neurobiol 33(6):615–620. https://doi.org/10.1111/j.1365-2990.2007.00907.x
Tsui CC, Copeland NG, Gilbert DJ, Jenkins NA, Barnes C, Worley PF (1996) Narp, a novel member of the pentraxin family, promotes neurite outgrowth and is dynamically regulated by neuronal activity. J Neurosci 16(8):2463–2478
Ubhi K, Low P, Masliah E (2011) Multiple system atrophy: a clinical and neuropathological perspective. Trends Neurosci 34(11):581–590. https://doi.org/10.1016/j.tins.2011.08.003
Vallortigara J, Rangarajan S, Whitfield D, Alghamdi A, Howlett D, Hortobagyi T, Johnson M, Attems J, Ballard C, Thomas A, O’Brien J, Aarsland D, Francis P (2014) Dynamin1 concentration in the prefrontal cortex is associated with cognitive impairment in Lewy body dementia. F1000Res 3:108. https://doi.org/10.12688/f1000research.3786.1
van Steenoven I, Majbour NK, Vaikath NN, Berendse HW, van der Flier WM, van de Berg WDJ, Teunissen CE, Lemstra AW, El-Agnaf OMA (2018) alpha-Synuclein species as potential cerebrospinal fluid biomarkers for dementia with lewy bodies. Mov Disord 33(11):1724–1733. https://doi.org/10.1002/mds.111
van Steenoven I, Noli B, Cocco C, Ferri GL, Oeckl P, Otto M, Koel-Simmelink MJA, Bridel C, van der Flier WM, Lemstra AW, Teunissen CE (2019) VGF peptides in cerebrospinal fluid of patients with dementia with lewy bodies. Int J Mol Sci. https://doi.org/10.3390/ijms20194674
van Steenoven I, Koel-Simmelink MJA, Vergouw LJM, Tijms BM, Piersma SR, Pham TV, Bridel C, Ferri GL, Cocco C, Noli B, Worley PF, Xiao MF, Xu D, Oeckl P, Otto M, van der Flier WM, de Jong FJ, Jimenez CR, Lemstra AW, Teunissen CE (2020) Identification of novel cerebrospinal fluid biomarker candidates for dementia with Lewy bodies: a proteomic approach. Mol Neurodegener 15(1):36. https://doi.org/10.1186/s13024-020-00388-2
Vasconcellos LF, Pereira JS (2015) Parkinson’s disease dementia: diagnostic criteria and risk factor review. J Clin Exp Neuropsychol 37(9):988–993. https://doi.org/10.1080/13803395.2015.1073227
Wallin A, Jennersjo C, Granerus AK (1999) Prevalence of dementia and regional brain syndromes in long-standing Parkinson’s disease. Parkinsonism Relat Disord 5(3):103–110. https://doi.org/10.1016/s1353-8020(99)00018-8
Wang Z, Danscher G, Kim YK, Dahlstrom A, Mook Jo S (2002) Inhibitory zinc-enriched terminals in the mouse cerebellum: double-immunohistochemistry for zinc transporter 3 and glutamate decarboxylase. Neurosci Lett 321(1–2):37–40. https://doi.org/10.1016/s0304-3940(01)02560-5
Wellington H, Paterson RW, Portelius E, Tornqvist U, Magdalinou N, Fox NC, Blennow K, Schott JM, Zetterberg H (2016) Increased CSF neurogranin concentration is specific to Alzheimer disease. Neurology 86(9):829–835. https://doi.org/10.1212/WNL.0000000000002423
Wennstrom M, Surova Y, Hall S, Nilsson C, Minthon L, Bostrom F, Hansson O, Nielsen HM (2013) Low CSF levels of both alpha-synuclein and the alpha-synuclein cleaving enzyme neurosin in patients with synucleinopathy. PLoS ONE 8(1):e53250. https://doi.org/10.1371/journal.pone.0053250
Xu D, Hopf C, Reddy R, Cho RW, Guo L, Lanahan A, Petralia RS, Wenthold RJ, O’Brien RJ, Worley P (2003) Narp and NP1 form heterocomplexes that function in developmental and activity-dependent synaptic plasticity. Neuron 39(3):513–528
Yakovleva T, Bazov I, Cebers G, Marinova Z, Hara Y, Ahmed A, Vlaskovska M, Johansson B, Hochgeschwender U, Singh IN, Bruce-Keller AJ, Hurd YL, Kaneko T, Terenius L, Ekstrom TJ, Hauser KF, Pickel VM, Bakalkin G (2006) Prodynorphin storage and processing in axon terminals and dendrites. FASEB J 20(12):2124–2126. https://doi.org/10.1096/fj.06-6174fje
Yamada M, Hashimoto T, Hayashi N, Higuchi M, Murakami A, Nakashima T, Maekawa S, Miyata S (2007) Synaptic adhesion molecule OBCAM; synaptogenesis and dynamic internalization. Brain Res 1165:5–14. https://doi.org/10.1016/j.brainres.2007.04.062
Zhang Z, Zhang S, Fu P, Lin K, Ko JK, Yung KK (2019) Roles of glutamate receptors in Parkinson’s disease. Int J Mol Sci. https://doi.org/10.3390/ijms20184391
Zhou B, Wen M, Yu WF, Zhang CL, Jiao L (2015) The diagnostic and differential diagnosis utility of cerebrospinal fluid alpha -synuclein levels in Parkinson’s disease: a meta-analysis. Parkinsons Dis 2015:567386. https://doi.org/10.1155/2015/567386
Funding
This work was funded by the Fondos de Investigaciones Sanitarias (PI18/00327 to OB) from the “Fondo Europeo de Desarrollo Regional (FEDER)”, Unión Europea, “Una manera de hacer Europa” and the “Instituto de Salud Carlos III, Ministerio de Economia y Competitividad, Gobierno de España” (ISCIII) and also by the Agència de Gestió d'Ajuts Universitaris i de Recerca (AGAUR), Spain & Regional Development Funds, EU Knowledge Industry Valorisation Grants-AGAUR-PRODUCTE (2019 PROD 00088 to OB).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
Dr Belbin is inventor of a patent application (EP18382175) pending approval entitled “Markers of synaptopathy in neurodegenerative disease”.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Cervantes González, A., Belbin, O. Fluid markers of synapse degeneration in synucleinopathies. J Neural Transm 129, 187–206 (2022). https://doi.org/10.1007/s00702-022-02467-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00702-022-02467-8