Methods for detecting toxic α-synuclein species as a biomarker for Parkinson’s disease

References

• Kasten M, Chade A, Tanner CM. Epidemiology of Parkinson's disease. Handb Clin Neurol. 2007;83:129–151.
   PubMedGoogle Scholar
• O'Hara DM, Kalia SK, Kalia LV. Emerging disease-modifying strategies targeting alpha-synuclein for the treatment of Parkinson's disease. Br J Pharmacol. 2018;175(15):3080–3089.
   PubMed Web of Science ®Google Scholar
• Trojanowski JQ, Goedert M, Iwatsubo T, et al. Fatal attractions: abnormal protein aggregation and neuron death in Parkinson's disease and Lewy body dementia. Cell Death Differ. 1998;5(10):832–837.
   PubMed Web of Science ®Google Scholar
• Klein C, Westenberger A. Genetics of Parkinson's disease. Cold Spring Harb Perspect Med. 2012;2(1):a008888.
   PubMed Web of Science ®Google Scholar
• Kalia LV, Lang AE, Hazrati L-N, et al. Clinical correlations with Lewy body pathology in LRRK2-related Parkinson disease. JAMA Neurol. 2015;72(1):100–105.
   PubMed Web of Science ®Google Scholar
• Doherty KM, Hardy J. Parkinson’s disease and the Lewy body conundrum. Mov Disord. 2013;28(6):702–704.
   PubMed Web of Science ®Google Scholar
• Lyons TJ, Basu A. Biomarkers in diabetes: hemoglobin A1c, vascular and tissue markers. Transl Res. 2012;159(4):303–312.
   PubMed Web of Science ®Google Scholar
• Farrell PM, Rosenstein BJ, White TB, et al. Guidelines for diagnosis of cystic fibrosis in newborns through older adults: Cystic Fibrosis Foundation consensus report. J Pediatr. 2008;153(2):S4–S14.
   PubMed Web of Science ®Google Scholar
• Lang AE, Lozano AM. Parkinson's disease. First of two parts. N Engl J Med. 1998;339(15):1044–1053.
   PubMed Web of Science ®Google Scholar
• Ansari KA, Johnson A. Olfactory function in patients with Parkinson's disease. J Chronic Dis. 1975;28(9):493–497.
   PubMedGoogle Scholar
• Doty RL. Olfaction in Parkinson's disease. Parkinsonism Relat Disord. 2007;13 (Suppl 3):S225–S228.
   PubMed Web of Science ®Google Scholar
• Braak H, Del Tredici K, Rüb U, et al. Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging. 2003;24(2):197–211.
   PubMed Web of Science ®Google Scholar
• Postuma RB, Berg D, Stern M, et al. MDS clinical diagnostic criteria for Parkinson's disease. Mov Disord. 2015;30(12):1591–1601.
   PubMed Web of Science ®Google Scholar
• Krismer F, Pinter B, Mueller C, et al. Sniffing the diagnosis: olfactory testing in neurodegenerative Parkinsonism. Parkinsonism Relat Disord. 2017;35:36–41.
   PubMed Web of Science ®Google Scholar
• Dauvilliers Y, Jennum P, Plazzi G. Rapid eye movement sleep behavior disorder and rapid eye movement sleep without atonia in narcolepsy. Sleep Med. 2013;14(8):775–781.
   PubMed Web of Science ®Google Scholar
• Schenck CH, Boeve BF, Mahowald MW. Delayed emergence of a parkinsonian disorder or dementia in 81% of older men initially diagnosed with idiopathic rapid eye movement sleep behavior disorder: a 16-year update on a previously reported series. Sleep Med. 2013;14(8):744–748.
   PubMed Web of Science ®Google Scholar
• Postuma RB, Gagnon JF, Vendette M, et al. Quantifying the risk of neurodegenerative disease in idiopathic REM sleep behavior disorder. Neurology. 2009;72(15):1296–1300.
   PubMed Web of Science ®Google Scholar
• Ellmore TM, Castriotta RJ, Hendley KL, et al. Altered nigrostriatal and nigrocortical functional connectivity in rapid eye movement sleep behavior disorder. Sleep. 2013;36(12):1885–1892.
   PubMed Web of Science ®Google Scholar
• Siddiqui MF, Rast S, Lynn MJ, et al. Autonomic dysfunction in Parkinson's disease: a comprehensive symptom survey. Parkinsonism Relat Disord. 2002;8(4):277–284.
   PubMed Web of Science ®Google Scholar
• Siddiqui IJ, Pervaiz N, Abbasi AA. The Parkinson disease gene SNCA: Evolutionary and structural insights with pathological implication. Sci Rep. 2016;6(1):24475.
   PubMed Web of Science ®Google Scholar
• Totterdell S, Hanger D, Meredith GE. The ultrastructural distribution of alpha-synuclein-like protein in normal mouse brain. Brain Res. 2004;1004(1–2):61–72.
   PubMed Web of Science ®Google Scholar
• Burré J. The synaptic function of α-Synuclein. JPD. 2015;5(4):699–713.
   Google Scholar
• Paik SR, Shin HJ, Lee JH, et al. Copper(II)-induced self-oligomerization of alpha-synuclein. Biochem J. 1999;340(3):821–828.
   PubMedGoogle Scholar
• Nielsen MS, Vorum H, Lindersson E, et al. Ca2+ binding to alpha-synuclein regulates ligand binding and oligomerization. J Biol Chem. 2001;276(25):22680–22684.
   PubMed Web of Science ®Google Scholar
• Ma KL, Song LK, Yuan YH, et al. The nuclear accumulation of alpha-synuclein is mediated by importin alpha and promotes neurotoxicity by accelerating the cell cycle. Neuropharmacology. 2014;82:132–142.
   PubMed Web of Science ®Google Scholar
• Periquet M, Fulga T, Myllykangas L, et al. Aggregated alpha-synuclein mediates dopaminergic neurotoxicity in vivo. J Neurosci. 2007;27(12):3338–3346.
   PubMed Web of Science ®Google Scholar
• Breydo L, Wu JW, Uversky VN. Α-synuclein misfolding and Parkinson's disease. Biochim Biophys Acta. 2012;1822(2):261–285.
   PubMed Web of Science ®Google Scholar
• Cabin DE, Shimazu K, Murphy D, et al. Synaptic vesicle depletion correlates with attenuated synaptic responses to prolonged repetitive stimulation in mice lacking alpha-synuclein. J Neurosci. 2002;22(20):8797–8807.
   PubMed Web of Science ®Google Scholar
• Abeliovich A, Schmitz Y, Fariñas I, et al. Mice lacking alpha-synuclein display functional deficits in the nigrostriatal dopamine system. Neuron. 2000;25(1):239–252.
   PubMed Web of Science ®Google Scholar
• Nemani VM, Lu W, Berge V, et al. Increased expression of alpha-synuclein reduces neurotransmitter release by inhibiting synaptic vesicle reclustering after endocytosis. Neuron. 2010;65(1):66–79.
   PubMed Web of Science ®Google Scholar
• Burré J, Sharma M, Tsetsenis T, et al. Alpha-synuclein promotes SNARE-complex assembly in vivo and in vitro. Science. 2010;329(5999):1663–1667.
   PubMed Web of Science ®Google Scholar
• Lee HJ, Khoshaghideh F, Lee S, et al. Impairment of microtubule-dependent trafficking by overexpression of alpha-synuclein. Eur J Neurosci. 2006;24(11):3153–3162.
   PubMed Web of Science ®Google Scholar
• Schaser AJ, Osterberg VR, Dent SE, et al. Alpha-synuclein is a DNA binding protein that modulates DNA repair with implications for Lewy body disorders. Sci Rep. 2019;9(1):10919.
   PubMedGoogle Scholar
• Beach TG, Adler CH, Sue LI, Arizona Parkinson’s Disease Consortium, et al. Multi-organ distribution of phosphorylated alpha-synuclein histopathology in subjects with Lewy body disorders. Acta Neuropathol. 2010;119(6):689–702.
   PubMed Web of Science ®Google Scholar
• Klingelhoefer L, Reichmann H. Pathogenesis of Parkinson disease–the gut-brain axis and environmental factors. Nat Rev Neurol. 2015;11(11):625–636.
   PubMed Web of Science ®Google Scholar
• Kim S, Kwon SH, Kam TI, et al. Transneuronal propagation of pathologic α-synuclein from the gut to the brain models Parkinson's disease. Neuron. 2019;103(4):627–641.
   PubMed Web of Science ®Google Scholar
• Holmqvist S, Chutna O, Bousset L, et al. Direct evidence of Parkinson pathology spread from the gastrointestinal tract to the brain in rats. Acta Neuropathol. 2014;128(6):805–820.
   PubMed Web of Science ®Google Scholar
• Mollenhauer B, Bowman FD, Drake D, et al. Antibody-based methods for the measurement of α-synuclein concentration in human cerebrospinal fluid - method comparison and round robin study. J Neurochem. 2019;149(1):126–138.
   PubMed Web of Science ®Google Scholar
• Eusebi P, Giannandrea D, Biscetti L, et al. Diagnostic utility of cerebrospinal fluid α-synuclein in Parkinson's disease: a systematic review and meta-analysis. Mov Disord. 2017;32(10):1389–1400.
   PubMed Web of Science ®Google Scholar
• Sako W, Murakami N, Izumi Y, et al. Reduced alpha-synuclein in cerebrospinal fluid in synucleinopathies: evidence from a meta-analysis. Mov Disord. 2014;29(13):1599–1605.
   PubMed Web of Science ®Google Scholar
• Gao L, Tang H, Nie K, et al. Cerebrospinal fluid alpha-synuclein as a biomarker for Parkinson's disease diagnosis: a systematic review and meta-analysis. Int J Neurosci. 2015;125(9):645–654.
   PubMed Web of Science ®Google Scholar
• Zhou B, Wen M, Yu WF, et al. The diagnostic and differential diagnosis utility of cerebrospinal fluid α-synuclein levels in Parkinson's disease: a meta-analysis. Parkinsons Dis. 2015;2015:567386.
   PubMed Web of Science ®Google Scholar
• Mollenhauer B, Caspell-Garcia CJ, Coffey CS, et al. for the PPMI study. Longitudinal analyses of cerebrospinal fluid α-Synuclein in prodromal and early Parkinson's disease. Mov Disord. 2019;34(9):1354–1364.
   PubMed Web of Science ®Google Scholar
• Foulds PG, Diggle P, Mitchell JD, et al. A longitudinal study on α-synuclein in blood plasma as a biomarker for Parkinson's disease. Sci Rep. 2013;3(1):2540.
   PubMedGoogle Scholar
• Ishii R, Tokuda T, Tatebe H, et al. Decrease in plasma levels of α-synuclein is evident in patients with Parkinson's disease after elimination of heterophilic antibody interference. PLoS One. 2015;10(4):e0123162.
   PubMed Web of Science ®Google Scholar
• Ding J, Zhang J, Wang X, et al. Relationship between the plasma levels of neurodegenerative proteins and motor subtypes of Parkinson's disease. J Neural Transm. 2017;124(3):353–360.
   PubMed Web of Science ®Google Scholar
• Gao H, Zhao Z, He Z, et al. Detection of Parkinson's disease through the peptoid recognizing α-synuclein in serum. ACS Chem Neurosci. 2019;10(3):1204–1208.
   PubMed Web of Science ®Google Scholar
• Simon RJ, Kania RS, Zuckermann RN, et al. Peptoids: a modular approach to drug discovery. Proc Natl Acad Sci USA. 1992;89(20):9367–9371.
   PubMed Web of Science ®Google Scholar
• Zhao Z, Zhu L, Li H, et al. Antiamyloidogenic activity of Aβ42-binding peptoid in modulating amyloid oligomerization. Small. 2017;13(1):1602857.
   Web of Science ®Google Scholar
• Udugamasooriya DG, Dineen SP, Brekken RA, et al. A peptoid “antibody surrogate” that antagonizes VEGF receptor 2 activity. J Am Chem Soc. 2008;130(17):5744–5752.
   PubMed Web of Science ®Google Scholar
• Ng ASL, Tan YJ, Lu Z, et al. Plasma alpha-synuclein detected by single molecule array is increased in PD. Ann Clin Transl Neurol. 2019;6(3):615–619.
   PubMed Web of Science ®Google Scholar
• Rhie A, Kirby L, Sayer N, et al. Characterization of 2′-fluoro-RNA aptamers that bind preferentially to disease-associated conformations of prion protein and inhibit conversion. J Biol Chem. 2003;278(41):39697–39705.
   PubMed Web of Science ®Google Scholar
• Qu J, Yu S, Zheng Y, et al. Aptamer and its applications in neurodegenerative diseases. Cell Mol Life Sci. 2017;74(4):683–695.
   PubMed Web of Science ®Google Scholar
• Chan HN, Xu D, Ho SL, et al. Highly sensitive quantification of Alzheimer's disease biomarkers by aptamer-assisted amplification. Theranostics. 2019;9(10):2939–2949.
   PubMed Web of Science ®Google Scholar
• Zheng Y, Qu J, Xue F, et al. Novel DNA aptamers for Parkinson's disease treatment inhibit α-synuclein aggregation and facilitate its degradation. Mol Ther Nucleic Acids. 2018;11:228–242.
   PubMedGoogle Scholar
• Ren X, Zhao Y, Xue F, et al. Exosomal DNA aptamer targeting α-synuclein aggregates reduced neuropathological deficits in a mouse Parkinson's disease model. Mol Ther Nucleic Acids. 2019;17:726–740.
   PubMedGoogle Scholar
• Tsukakoshi K, Abe K, Sode K, et al. Selection of DNA aptamers that recognize alpha-synuclein oligomers using a competitive screening method. Anal Chem. 2012;84(13):5542–5547.
   PubMed Web of Science ®Google Scholar
• Ikemura M, Saito Y, Sengoku R, et al. Lewy body pathology involves cutaneous nerves. J Neuropathol Exp Neurol. 2008;67(10):945–953.
   PubMed Web of Science ®Google Scholar
• Gelpi E, Navarro-Otano J, Tolosa E, et al. Multiple organ involvement by alpha-synuclein pathology in Lewy body disorders. Mov Disord. 2014;29(8):1010–1018.
   PubMed Web of Science ®Google Scholar
• Gibbons CH, Wang N, Freeman R. Cutaneous alpha-synuclein from paraffin embedded autopsy specimens in Parkinson's disease. JPD. 2017;7(3):503–509.
   Google Scholar
• Kim JY, Illigens BM, McCormick MP, et al. Alpha-synuclein in skin nerve fibers as a biomarker for alpha-synucleinopathies. J Clin Neurol. 2019;15(2):135–142.
   PubMed Web of Science ®Google Scholar
• Wang N, Gibbons CH, Lafo J, et al. α-Synuclein in cutaneous autonomic nerves. Neurology. 2013;81(18):1604–1610.
   PubMed Web of Science ®Google Scholar
• Hoepken HH, Gispert S, Azizov M, et al. Parkinson patient fibroblasts show increased alpha-synuclein expression. Exp Neurol. 2008;212(2):307–313.
   PubMed Web of Science ®Google Scholar
• Zuev VA, Dyatlova AS, Lin’kova NS, et al. Skin fibroblasts as the object for clinical diagnosis of Parkinson's disease in persons of different ages. Bull Exp Biol Med. 2019;167(1):177–181.
   PubMed Web of Science ®Google Scholar
• Shannon KM, Keshavarzian A, Dodiya HB, et al. Is alpha-synuclein in the colon a biomarker for premotor Parkinson's disease? Evidence from 3 cases. Mov Disord. 2012;27(6):716–719.
   PubMed Web of Science ®Google Scholar
• Shannon KM, Keshavarzian A, Mutlu E, et al. Alpha-synuclein in colonic submucosa in early untreated Parkinson's disease. Mov Disord. 2012;27(6):709–715.
   PubMed Web of Science ®Google Scholar
• Pouclet H, Lebouvier T, Coron E, et al. Analysis of colonic alpha-synuclein pathology in multiple system atrophy. Parkinsonism Relat Disord. 2012;18(7):893–895.
   PubMed Web of Science ®Google Scholar
• Hilton D, Stephens M, Kirk L, et al. Accumulation of α-synuclein in the bowel of patients in the pre-clinical phase of Parkinson's disease. Acta Neuropathol. 2014;127(2):235–241.
   PubMed Web of Science ®Google Scholar
• Kim C, Lee SJ. Controlling the mass action of alpha-synuclein in Parkinson's disease. J Neurochem. 2008;107(2):303–316.
   PubMed Web of Science ®Google Scholar
• Lashuel HA, Overk CR, Oueslati A, et al. The many faces of α-synuclein: from structure and toxicity to therapeutic target. Nat Rev Neurosci. 2013;14(1):38–48.
   PubMed Web of Science ®Google Scholar
• Conway KA, Lee SJ, Rochet JC, et al. Acceleration of oligomerization, not fibrillization, is a shared property of both alpha-synuclein mutations linked to early-onset Parkinson's disease: implications for pathogenesis and therapy. Proc Natl Acad Sci USA. 2000;97(2):571–576.
   PubMed Web of Science ®Google Scholar
• Fredenburg RA, Rospigliosi C, Meray RK, et al. The impact of the E46K mutation on the properties of alpha-synuclein in its monomeric and oligomeric states. Biochemistry. 2007;46(24):7107–7118.
   PubMed Web of Science ®Google Scholar
• Cremades N, Cohen SI, Deas E, et al. Direct observation of the interconversion of normal and toxic forms of α-synuclein. Cell. 2012;149(5):1048–1059.
   PubMed Web of Science ®Google Scholar
• Ingelsson M. Alpha-synuclein oligomers-neurotoxic molecules in Parkinson's disease and other Lewy body disorders. Front Neurosci. 2016;10:408.
   PubMed Web of Science ®Google Scholar
• Hsu LJ, Sagara Y, Arroyo A, et al. Alpha-synuclein promotes mitochondrial deficit and oxidative stress. Am J Pathol. 2000;157(2):401–410.
   PubMed Web of Science ®Google Scholar
• Devi L, Raghavendran V, Prabhu BM, et al. Mitochondrial import and accumulation of alpha-synuclein impair complex I in human dopaminergic neuronal cultures and Parkinson disease brain. J Biol Chem. 2008;283(14):9089–9100.
   PubMed Web of Science ®Google Scholar
• Nakamura K, Nemani VM, Azarbal F, et al. Direct membrane association drives mitochondrial fission by the Parkinson disease-associated protein alpha-synuclein. J Biol Chem. 2011;286(23):20710–20726.
   PubMed Web of Science ®Google Scholar
• Bourdenx M, Bezard E, Dehay B. Lysosomes and α-synuclein form a dangerous duet leading to neuronal cell death. Front Neuroanat. 2014;8:83.
   PubMed Web of Science ®Google Scholar
• Alim MA, Ma QL, Takeda K, et al. Demonstration of a role for alpha-synuclein as a functional microtubule-associated protein. JAD. 2004;6(4):435–442.
   Google Scholar
• Scott DA, Tabarean I, Tang Y, et al. A pathologic cascade leading to synaptic dysfunction in alpha-synuclein-induced neurodegeneration. J Neurosci. 2010;30(24):8083–8095.
   PubMed Web of Science ®Google Scholar
• Danzer KM, Haasen D, Karow AR, et al. Different species of alpha-synuclein oligomers induce calcium influx and seeding. J Neurosci. 2007;27(34):9220–9232.
   PubMed Web of Science ®Google Scholar
• Tetzlaff JE, Putcha P, Outeiro TF, et al. CHIP targets toxic alpha-Synuclein oligomers for degradation. J Biol Chem. 2008;283(26):17962–17968.
   PubMed Web of Science ®Google Scholar
• Winner B, Jappelli R, Maji SK, et al. In vivo demonstration that α-synuclein oligomers are toxic. Proceedings of the National Academy of Sciences. 2011;108(10):4194–4199.
   PubMed Web of Science ®Google Scholar
• Dimant H, Kalia SK, Kalia LV, et al. Direct detection of alpha synuclein oligomers in vivo. Acta Neuropathol Commun. 2013;1(1):6.
   PubMedGoogle Scholar
• Janezic S, Threlfell S, Dodson PD, et al. Deficits in dopaminergic transmission precede neuron loss and dysfunction in a new Parkinson model. Proc Natl Acad Sci USA. 2013;110(42):E4016–25.
   PubMed Web of Science ®Google Scholar
• Giasson BI, Duda JE, Quinn SM, et al. Neuronal alpha-synucleinopathy with severe movement disorder in mice expressing A53T human alpha-synuclein. Neuron. 2002;34(4):521–533.
   PubMed Web of Science ®Google Scholar
• Sharon R, Bar-Joseph I, Frosch MP, et al. The formation of highly soluble oligomers of alpha-synuclein is regulated by fatty acids and enhanced in Parkinson's disease. Neuron. 2003;37(4):583–595.
   PubMed Web of Science ®Google Scholar
• Lee HJ, Suk JE, Bae EJ, et al. Assembly-dependent endocytosis and clearance of extracellular alpha-synuclein. Int J Biochem Cell Biol. 2008;40(9):1835–1849.
   PubMed Web of Science ®Google Scholar
• Desplats P, Lee HJ, Bae EJ, et al. Inclusion formation and neuronal cell death through neuron-to-neuron transmission of alpha-synuclein. Proc Natl Acad Sci USA. 2009;106(31):13010–13015.
   PubMed Web of Science ®Google Scholar
• Aulić S, Le TT, Moda F, et al. Defined α-synuclein prion-like molecular assemblies spreading in cell culture. BMC Neurosci. 2014;15(1):69.
   PubMedGoogle Scholar
• Reyes JF, Olsson TT, Lamberts JT, et al. A cell culture model for monitoring α-synuclein cell-to-cell transfer. Neurobiol Dis. 2015;77:266–275.
   PubMed Web of Science ®Google Scholar
• Hansen C, Angot E, Bergström AL, et al. α-Synuclein propagates from mouse brain to grafted dopaminergic neurons and seeds aggregation in cultured human cells. J Clin Invest. 2011;121(2):715–725.
   PubMed Web of Science ®Google Scholar
• Tran HT, Chung CH, Iba M, et al. Α-synuclein immunotherapy blocks uptake and templated propagation of misfolded α-synuclein and neurodegeneration. Cell Rep. 2014;7(6):2054–2065.
   PubMed Web of Science ®Google Scholar
• Recasens A, Dehay B, Bové J, et al. Lewy body extracts from Parkinson disease brains trigger α-synuclein pathology and neurodegeneration in mice and monkeys. Ann Neurol. 2014;75(3):351–362.
   PubMed Web of Science ®Google Scholar
• Mougenot AL, Nicot S, Bencsik A, et al. Prion-like acceleration of a synucleinopathy in a transgenic mouse model. Neurobiol Aging. 2012;33(9):2225–2228.
   PubMed Web of Science ®Google Scholar
• Shimozawa A, Ono M, Takahara D, et al. Propagation of pathological α-synuclein in marmoset brain. Acta Neuropathol Commun. 2017;5(1):12.
   PubMedGoogle Scholar
• Rey NL, Petit GH, Bousset L, et al. Transfer of human α-synuclein from the olfactory bulb to interconnected brain regions in mice. Acta Neuropathol. 2013;126(4):555–573.
   PubMed Web of Science ®Google Scholar
• Dagher A, Zeighami Y. Testing the protein propagation hypothesis of Parkinson disease. J Exp Neurosci. 2018;12:117906951878671.
   Web of Science ®Google Scholar
• Kordower JH, Chu Y, Hauser RA, et al. Lewy body-like pathology in long-term embryonic nigral transplants in Parkinson's disease. Nat Med. 2008;14(5):504–506.
   PubMed Web of Science ®Google Scholar
• Li JY, Englund E, Holton JL, et al. Lewy bodies in grafted neurons in subjects with Parkinson's disease suggest host-to-graft disease propagation. Nat Med. 2008;14(5):501–503.
   PubMed Web of Science ®Google Scholar
• Fujiwara H, Hasegawa M, Dohmae N, et al. Alpha-synuclein is phosphorylated in synucleinopathy lesions. Nat Cell Biol. 2002;4(2):160–164.
   PubMed Web of Science ®Google Scholar
• Oueslati A. Implication of alpha-synuclein phosphorylation at S129 in synucleinopathies: what have we learned in the last decade? JPD. 2016;6(1):39–51.
   Google Scholar
• Chen L, Feany MB. Alpha-synuclein phosphorylation controls neurotoxicity and inclusion formation in a Drosophila model of Parkinson disease. Nat Neurosci. 2005;8(5):657–663.
   PubMed Web of Science ®Google Scholar
• Gorbatyuk OS, Li S, Sullivan LF, et al. The phosphorylation state of Ser-129 in human alpha-synuclein determines neurodegeneration in a rat model of Parkinson disease. Proc Natl Acad Sci USA. 2008;105(2):763–768.
   PubMed Web of Science ®Google Scholar
• Azeredo da Silveira S, Schneider BL, Cifuentes-Diaz C, et al. Phosphorylation does not prompt, nor prevent, the formation of alpha-synuclein toxic species in a rat model of Parkinson's disease. Hum Mol Genet. 2009;18(5):872–887.
   PubMed Web of Science ®Google Scholar
• McFarland NR, Fan Z, Xu K, et al. Alpha-synuclein S129 phosphorylation mutants do not alter nigrostriatal toxicity in a rat model of Parkinson disease. J Neuropathol Exp Neurol. 2009;68(5):515–524.
   PubMed Web of Science ®Google Scholar
• Shahnawaz M, Tokuda T, Waragai M, et al. Development of a biochemical diagnosis of Parkinson disease by detection of alpha-synuclein misfolded aggregates in cerebrospinal fluid. JAMA Neurol. 2017;74(2):163–172.
   PubMed Web of Science ®Google Scholar
• Saborio GP, Permanne B, Soto C. Sensitive detection of pathological prion protein by cyclic amplification of protein misfolding. Nature. 2001;411(6839):810–813.
   PubMed Web of Science ®Google Scholar
• Fairfoul G, McGuire LI, Pal S, et al. Alpha-synuclein RT-QuIC in the CSF of patients with alpha-synucleinopathies. Ann Clin Transl Neurol. 2016;3(10):812–818.
   PubMed Web of Science ®Google Scholar
• Foutz A, Appleby BS, Hamlin C, et al. Diagnostic and prognostic value of human prion detection in cerebrospinal fluid. Ann Neurol. 2017;81(1):79–92.
   PubMed Web of Science ®Google Scholar
• Orru CD, Groveman BR, Hughson AG, et al. Rapid and sensitive RT-QuIC detection of human Creutzfeldt-Jakob disease using cerebrospinal fluid. MBio. 2015;6(1):e02451-14.
   PubMed Web of Science ®Google Scholar
• Groveman BR, Orrù CD, Hughson AG, et al. Rapid and ultra-sensitive quantitation of disease-associated α-synuclein seeds in brain and cerebrospinal fluid by αSyn RT-QuIC. Acta Neuropathol Commun. 2018;6(1):7.
   PubMedGoogle Scholar
• Kakuda K, Ikenaka K, Araki K, et al. Ultrasonication-based rapid amplification of α-synuclein aggregates in cerebrospinal fluid. Sci Rep. 2019;9:6001.
   Google Scholar
• Söderberg O, Gullberg M, Jarvius M, et al. Direct observation of individual endogenous protein complexes in situ by proximity ligation. Nat Methods. 2006;3(12):995–1000.
   PubMed Web of Science ®Google Scholar
• Roberts RF, Wade-Martins R, Alegre-Abarrategui J. Direct visualization of alpha-synuclein oligomers reveals previously undetected pathology in Parkinson's disease brain. Brain. 2015;138(6):1642–1657.
   PubMedGoogle Scholar
• Ruffmann C, Bengoa-Vergniory N, Poggiolini I, et al. Detection of alpha-synuclein conformational variants from gastro-intestinal biopsy tissue as a potential biomarker for Parkinson's disease. Neuropathol Appl Neurobiol. 2018;44(7):722–736.
   PubMed Web of Science ®Google Scholar
• Emadi S, Kasturirangan S, Wang MS, et al. Detecting morphologically distinct oligomeric forms of alpha-synuclein. J Biol Chem. 2009;284(17):11048–11058.
   PubMed Web of Science ®Google Scholar
• Williams SM, Schulz P, Sierks MR. Oligomeric α-synuclein and β-amyloid variants as potential biomarkers for Parkinson's and Alzheimer's diseases. Eur J Neurosci. 2016;43(1):3–16.
   PubMed Web of Science ®Google Scholar
• Tian C, Liu G, Gao L, et al. Erythrocytic α-synuclein as a potential biomarker for Parkinson's disease. Transl Neurodegener. 2019;8(1):15.
   PubMedGoogle Scholar
• Wang Y, Shi M, Chung KA, et al. Phosphorylated α-synuclein in Parkinson's disease. Sci Transl Med. 2012;4(121):121ra20–121ra20.
   PubMed Web of Science ®Google Scholar
• Majbour NK, Vaikath NN, van Dijk KD, et al. Oligomeric and phosphorylated alpha-synuclein as potential CSF biomarkers for Parkinson's disease. Mol Neurodegener. 2016;11:7.
   PubMed Web of Science ®Google Scholar
• Wang X, Yu S, Li F, et al. Detection of α-synuclein oligomers in red blood cells as a potential biomarker of Parkinson's disease. Neurosci Lett. 2015;599:115–119.
   PubMed Web of Science ®Google Scholar
• Daniele S, Frosini D, Pietrobono D, et al. α-Synuclein heterocomplexes with β-amyloid are increased in red blood cells of Parkinson's disease patients and correlate with disease severity. Front Mol Neurosci. 2018;11:53.
   PubMed Web of Science ®Google Scholar
• Al-Nimer MS, Mshatat SF, Abdulla HI. Saliva α-synuclein and a high extinction coefficient protein: a novel approach in assessment biomarkers of Parkinson's disease. North Am J Med Sci. 2014;6(12):633–637.
   PubMedGoogle Scholar
• Donadio V, Incensi A, Piccinini C, et al. Skin nerve misfolded α-synuclein in pure autonomic failure and Parkinson disease. Ann Neurol. 2016;79(2):306–316.
   PubMed Web of Science ®Google Scholar
• Donadio V, Incensi A, Leta V, et al. Skin nerve α-synuclein deposits: a biomarker for idiopathic Parkinson disease. Neurology. 2014;82(15):1362–1369.
   PubMed Web of Science ®Google Scholar
• Doppler K, Ebert S, Uçeyler N, et al. Cutaneous neuropathy in Parkinson's disease: a window into brain pathology. Acta Neuropathol. 2014;128(1):99–109.
   PubMed Web of Science ®Google Scholar
• Antelmi E, Donadio V, Incensi A, et al. Skin nerve phosphorylated α-synuclein deposits in idiopathic REM sleep behavior disorder. Neurology. 2017;88(22):2128–2131.
   PubMed Web of Science ®Google Scholar
• Haga R, Sugimoto K, Nishijima H, et al. Clinical utility of skin biopsy in differentiating between Parkinson's disease and multiple system atrophy. Parkinsons Dis. 2015;2015:167038.
   PubMed Web of Science ®Google Scholar
• Zange L, Noack C, Hahn K, et al. Phosphorylated α-synuclein in skin nerve fibres differentiates Parkinson's disease from multiple system atrophy. Brain. 2015;138(8):2310–2321.
   PubMedGoogle Scholar
• Donadio V, Incensi A, Del Sorbo F, et al. Skin nerve phosphorylated α-synuclein deposits in Parkinson disease with orthostatic hypotension. J Neuropathol Exp Neurol. 2018;77(10):942–949.
   PubMed Web of Science ®Google Scholar
• Donadio V, Incensi A, El-Agnaf O, et al. Skin alpha-synuclein deposits differ in clinical variants of synucleinopathy: an in vivo study. Sci Rep. 2018;8(1):14246.
   PubMed Web of Science ®Google Scholar
• Tsukita K, Sakamaki-Tsukita H, Tanaka K, et al. Value of in vivo α-synuclein deposits in Parkinson's disease: a systematic review and meta-analysis. Mov Disord. 2019;34(10):1452–1463.
   PubMed Web of Science ®Google Scholar
• Donadio V, Doppler K, Incensi A, et al. Abnormal α-synuclein deposits in skin nerves: intra- and inter-laboratory reproducibility. Eur J Neurol. 2019;26(10):1245–1251.
   PubMed Web of Science ®Google Scholar
• Del Tredici K, Hawkes CH, Ghebremedhin E, et al. Lewy pathology in the submandibular gland of individuals with incidental Lewy body disease and sporadic Parkinson's disease. Acta Neuropathol. 2010;119(6):703–713.
   PubMed Web of Science ®Google Scholar
• Beach TG, Adler CH, Dugger BN, Arizona Parkinson's Disease Consortium, et al. Submandibular gland biopsy for the diagnosis of Parkinson disease. J Neuropathol Exp Neurol. 2013;72(2):130–136.
   PubMed Web of Science ®Google Scholar
• Folgoas E, Lebouvier T, Leclair-Visonneau L, et al. Diagnostic value of minor salivary glands biopsy for the detection of Lewy pathology. Neurosci Lett. 2013;551:62–64.
   PubMed Web of Science ®Google Scholar
• He Y, Yu Z, Chen S. Alpha-synuclein nitration and its implications in Parkinson's disease. ACS Chem Neurosci. 2019;10(2):777–782.
   PubMed Web of Science ®Google Scholar
• Ma LY, Gao LY, Li X, et al. Nitrated alpha-synuclein in minor salivary gland biopsies in Parkinson's disease. Neurosci Lett. 2019;704:45–49.
   PubMed Web of Science ®Google Scholar
• Lebouvier T, Chaumette T, Damier P, et al. Pathological lesions in colonic biopsies during Parkinson's disease. Gut. 2008;57(12):1741–1743.
   PubMed Web of Science ®Google Scholar
• Lebouvier T, Coron E, Chaumette T, et al. Routine colonic biopsies as a new tool to study the enteric nervous system in living patients. Neurogastroenterol Motil. 2010;22(1):e11–e14.
   PubMed Web of Science ®Google Scholar
• Pouclet H, Lebouvier T, Coron E, et al. A comparison between colonic submucosa and mucosa to detect Lewy pathology in Parkinson's disease. Neurogastroenterol Motil. 2012;24(4):e202–e205.
   PubMed Web of Science ®Google Scholar
• Pouclet H, Lebouvier T, Coron E, et al. A comparison between rectal and colonic biopsies to detect Lewy pathology in Parkinson's disease. Neurobiol Dis. 2012;45(1):305–309.
   PubMed Web of Science ®Google Scholar
• Stokholm MG, Danielsen EH, Hamilton-Dutoit SJ, et al. Pathological α-synuclein in gastrointestinal tissues from prodromal Parkinson disease patients. Ann Neurol. 2016;79(6):940–949.
   PubMed Web of Science ®Google Scholar
• Liu FT, Ge JJ, Wu JJ, et al. Clinical, dopaminergic, and metabolic correlations in Parkinson disease: a dual-tracer PET study. Clin Nucl Med. 2018;43(8):562–571.
   PubMed Web of Science ®Google Scholar
• Cui M. Past and recent progress of molecular imaging probes for beta-amyloid plaques in the brain. CMC. 2013;21(1):82–112.
   Web of Science ®Google Scholar
• Fodero-Tavoletti MT, Mulligan RS, Okamura N, et al. In vitro characterisation of BF227 binding to α-synuclein/Lewy bodies. Eur J Pharmacol. 2009;617(1–3):54–58.
   Google Scholar
• Fodero-Tavoletti MT, Smith DP, McLean CA, et al. In vitro characterization of Pittsburgh compound-B binding to Lewy bodies. J Neurosci. 2007;27(39):10365–10371.
   PubMed Web of Science ®Google Scholar
• Levigoureux E, Lancelot S, Bouillot C, et al. Binding of the PET radiotracer [(1)(8)F]BF227 does not reflect the presence of alpha-synuclein aggregates in transgenic mice. CAR. 2014;11(10):955–960.
   Google Scholar
• Yu L, Cui J, Padakanti PK, et al. Synthesis and in vitro evaluation of α-synuclein ligands. Bioorg Med Chem. 2012;20(15):4625–4634.
   PubMed Web of Science ®Google Scholar
• Bagchi DP, Yu L, Perlmutter JS, et al. Binding of the radio ligand SIL23 to α-synuclein fibrils in Parkinson disease brain tissue establishes feasibility and screening approaches for developing a Parkinson disease imaging agent. PLoS One. 2013;8(2):e55031.
   PubMed Web of Science ®Google Scholar
• Zhang X, Jin H, Padakanti PK, et al. Radiosynthesis and in vivo evaluation of two PET radio ligands for imaging alpha-synuclein. Appl Sci (Basel). 2014;4(1):66–78.
   PubMed Web of Science ®Google Scholar
• De Groef L, Cordeiro MF. Is the eye an extension of the brain in central nervous system disease? J Ocul Pharmacol Ther. 2018;34(1–2):129–133.
   PubMed Web of Science ®Google Scholar
• Leger F, Fernagut PO, Canron MH, et al. Protein aggregation in the aging retina. J Neuropathol Exp Neurol. 2011;70(1):63–68.
   PubMed Web of Science ®Google Scholar
• Martínez-Navarrete GC, Martín-Nieto J, Esteve-Rudd J, et al. Alpha synuclein gene expression profile in the retina of vertebrates. Mol Vis. 2007;13:949–961.
   PubMed Web of Science ®Google Scholar
• Beach TG, Carew J, Serrano G, et al. Phosphorylated α-synuclein-immunoreactive retinal neuronal elements in Parkinson's disease subjects. Neurosci Lett. 2014;571:34–38.
   PubMed Web of Science ®Google Scholar
• Bodis-Wollner I, Kozlowski PB, Glazman S, et al. α-synuclein in the inner retina in parkinson disease. Ann Neurol. 2014;75(6):964–966.
   PubMed Web of Science ®Google Scholar
• Ortuño-Lizarán I, Beach TG, Serrano GE, et al. Phosphorylated α-synuclein in the retina is a biomarker of Parkinson's disease pathology severity. Mov Disord. 2018;33(8):1315–1324.
   PubMed Web of Science ®Google Scholar
• Koronyo Y, Salumbides BC, Black KL, et al. Alzheimer's disease in the retina: imaging retinal aβ plaques for early diagnosis and therapy assessment. Neurodegenerative Dis. 2012;10(1–4):285–293.
   PubMed Web of Science ®Google Scholar
• Singh PK, Kotia V, Ghosh D, et al. Curcumin modulates α-synuclein aggregation and toxicity. ACS Chem Neurosci. 2013;4(3):393–407.
   PubMed Web of Science ®Google Scholar
• Wagner J, Ryazanov S, Leonov A, et al. Anle138b: a novel oligomer modulator for disease-modifying therapy of neurodegenerative diseases such as prion and Parkinson's disease. Acta Neuropathol. 2013;125(6):795–813.
   PubMed Web of Science ®Google Scholar
• Veys L, Vandenabeele M, Ortuño-Lizarán I, et al. Retinal α-synuclein deposits in Parkinson's disease patients and animal models. Acta Neuropathol. 2019;137(3):379–395.
   PubMed Web of Science ®Google Scholar
• Saito Y. Oxidized DJ-1 as a possible biomarker of Parkinson's disease. J Clin Biochem Nutr. 2014;54(3):138–144.
   PubMed Web of Science ®Google Scholar
• Parnetti L, Paciotti S, Eusebi P, et al. Cerebrospinal fluid β-glucocerebrosidase activity is reduced in parkinson's disease patients. Mov Disord. 2017;32(10):1423–1431.
   PubMed Web of Science ®Google Scholar
• Scalzo P, Kümmer A, Bretas TL, et al. Serum levels of brain-derived neurotrophic factor correlate with motor impairment in Parkinson's disease. J Neurol. 2010;257(4):540–545.
   PubMed Web of Science ®Google Scholar
• Hall S, Janelidze S, Surova Y, et al. Cerebrospinal fluid concentrations of inflammatory markers in Parkinson's disease and atypical parkinsonian disorders. Sci Rep. 2018;8(1):13276.
   PubMedGoogle Scholar
• Shahnawaz M, Mukherjee A, Pritzkow S, et al. Discriminating α-synuclein strains in Parkinson's disease and multiple system atrophy. Nature. 2020;578(7794):273–277.
   Google Scholar