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Neuronal activity modulates alpha-synuclein aggregation and spreading in organotypic brain slice cultures and in vivo

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Abstract

Alpha-synuclein (αSyn) preformed fibrils (PFF) induce endogenous αSyn aggregation leading to reduced synaptic transmission. Neuronal activity modulates release of αSyn; however, whether neuronal activity regulates the spreading of αSyn pathology remains elusive. Here, we established a hippocampal slice culture system from wild-type (WT) mice and found that both Ca2+ influx and the uptake of αSyn PFF were higher in the CA3 than in the CA1 sub-region. Pharmacologically enhancing neuronal activity substantially increased αSyn pathology in αSyn PFF-treated hippocampal or midbrain slice cultures and accelerated dopaminergic neuron degeneration. Consistently, neuronal hyperactivity promoted PFF trafficking along axons/dendrites within microfluidic chambers. Unexpectedly, enhancing neuronal activity in LRRK2 G2019S mutant slice cultures further increased αSyn pathology, especially with more Lewy body (LB) forming than in WT slice cultures. Finally, following injection of αSyn PFF and chemogenetic modulators into the dorsal striatum of WT mice, both motor behavior and αSyn pathology were exacerbated likely by enhancing neuronal activity, since they were ameliorated by reducing neuronal activity. Thus, a greater understanding of the impact of neuronal activity on αSyn aggregation and spreading, as well as dopaminergic neuronal vulnerability, may provide new therapeutic strategies for patients with LB disease (LBD).

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References

  1. Abeliovich A, Schmitz Y, Farinas I, Choi-Lundberg D, Ho WH, Castillo PE et al (2000) Mice lacking alpha-synuclein display functional deficits in the nigrostriatal dopamine system. Neuron 25:239–252. https://doi.org/10.1016/s0896-6273(00)80886-7

    Article  CAS  PubMed  Google Scholar 

  2. Arber C, Lovejoy C, Wray S (2017) Stem cell models of Alzheimer's disease: progress and challenges. Alzheimers Res Ther 9:42. https://doi.org/10.1186/s13195-017-0268-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Bassil F, Brown HJ, Pattabhiraman S, Iwasyk JE, Maghames CM, Meymand ES et al (2020) Amyloid-beta (Abeta) plaques promote seeding and spreading of alpha-synuclein and tau in a mouse model of lewy body disorders with abeta pathology. Neuron 105(260–275):e266. https://doi.org/10.1016/j.neuron.2019.10.010

    Article  CAS  Google Scholar 

  4. Bove J, Prou D, Perier C, Przedborski S (2005) Toxin-induced models of Parkinson's disease. NeuroRx 2:484–494. https://doi.org/10.1602/neurorx.2.3.484

    Article  PubMed  PubMed Central  Google Scholar 

  5. 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 24:197–211. https://doi.org/10.1016/s0197-4580(02)00065-9

    Article  PubMed  Google Scholar 

  6. Busche MA, Konnerth A (2016) Impairments of neural circuit function in Alzheimer's disease. Philos Trans R Soc Lond B Biol Sci. https://doi.org/10.1098/rstb.2015.0429

    Article  PubMed  PubMed Central  Google Scholar 

  7. Caputo A, Liang Y, Raabe TD, Lo A, Horvath M, Zhang B et a. (2020) Snca-GFP knock-in mice reflect patterns of endogenous expression and pathological seeding. ENeuro. https://doi.org/10.1523/ENEURO.0007-20.2020

    Article  PubMed  PubMed Central  Google Scholar 

  8. Chen H, Ritz B (2018) The search for environmental causes of Parkinson's disease: moving forward. J Parkinsons Dis 8:S9–S17. https://doi.org/10.3233/JPD-181493

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Choi SH, Kim YH, Hebisch M, Sliwinski C, Lee S, D'Avanzo C et al (2014) A three-dimensional human neural cell culture model of Alzheimer's disease. Nature 515:274–278. https://doi.org/10.1038/nature13800

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Croft CL, Cruz PE, Ryu DH, Ceballos-Diaz C, Strang KH, Woody BM et al (2019) rAAV-based brain slice culture models of Alzheimer's and Parkinson's disease inclusion pathologies. J Exp Med 216:539–555. https://doi.org/10.1084/jem.20182184

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Croft CL, Futch HS, Moore BD, Golde TE (2019) Organotypic brain slice cultures to model neurodegenerative proteinopathies. Mol Neurodegener 14:45. https://doi.org/10.1186/s13024-019-0346-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Croft CL, Kurbatskaya K, Hanger DP, Noble W (2017) Inhibition of glycogen synthase kinase-3 by BTA-EG4 reduces tau abnormalities in an organotypic brain slice culture model of Alzheimer's disease. Sci Rep 7:7434. https://doi.org/10.1038/s41598-017-07906-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Dong XX, Wang Y, Qin ZH (2009) Molecular mechanisms of excitotoxicity and their relevance to pathogenesis of neurodegenerative diseases. Acta Pharmacol Sin 30:379–387. https://doi.org/10.1038/aps.2009.24

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Duff K, Noble W, Gaynor K, Matsuoka Y (2002) Organotypic slice cultures from transgenic mice as disease model systems. J Mol Neurosci 19:317–320. https://doi.org/10.1385/JMN:19:3:317

    Article  CAS  PubMed  Google Scholar 

  15. Elfarrash S, Jensen NM, Ferreira N, Betzer C, Thevathasan JV, Diekmann R et al (2019) Organotypic slice culture model demonstrates inter-neuronal spreading of alpha-synuclein aggregates. Acta Neuropathol Commun 7:213. https://doi.org/10.1186/s40478-019-0865-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Emmanouilidou E, Melachroinou K, Roumeliotis T, Garbis SD, Ntzouni M, Margaritis LH et al (2010) Cell-produced alpha-synuclein is secreted in a calcium-dependent manner by exosomes and impacts neuronal survival. J Neurosci 30:6838–6851. https://doi.org/10.1523/JNEUROSCI.5699-09.2010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Emmanouilidou E, Minakaki G, Keramioti MV, Xylaki M, Balafas E, Chrysanthou-Piterou M et al (2016) GABA transmission via ATP-dependent K+ channels regulates alpha-synuclein secretion in mouse striatum. Brain 139:871–890. https://doi.org/10.1093/brain/awv403

    Article  PubMed  Google Scholar 

  18. Fahn S (2003) Description of Parkinson's disease as a clinical syndrome. Ann N Y Acad Sci 991:1–14. https://doi.org/10.1111/j.1749-6632.2003.tb07458.x

    Article  CAS  PubMed  Google Scholar 

  19. Fujiwara H, Hasegawa M, Dohmae N, Kawashima A, Masliah E, Goldberg MS et al (2002) alpha-Synuclein is phosphorylated in synucleinopathy lesions. Nat Cell Biol 4:160–164. https://doi.org/10.1038/ncb748

    Article  CAS  PubMed  Google Scholar 

  20. Giasson BI, Murray IV, Trojanowski JQ, Lee VM (2001) A hydrophobic stretch of 12 amino acid residues in the middle of alpha-synuclein is essential for filament assembly. The Journal of biological chemistry 276:2380–2386. https://doi.org/10.1074/jbc.M008919200

    Article  CAS  PubMed  Google Scholar 

  21. Gogolla N, Galimberti I, DePaola V, Caroni P (2006) Preparation of organotypic hippocampal slice cultures for long-term live imaging. Nat Protoc 1:1165–1171. https://doi.org/10.1038/nprot.2006.168

    Article  CAS  PubMed  Google Scholar 

  22. Gong W, Sencar J, Bakkum DJ, Jackel D, Obien ME, Radivojevic M et al (2016) Multiple single-unit long-term tracking on organotypic hippocampal slices using high-density microelectrode arrays. Front Neurosci 10:537. https://doi.org/10.3389/fnins.2016.00537

    Article  PubMed  PubMed Central  Google Scholar 

  23. Guo JL, Covell DJ, Daniels JP, Iba M, Stieber A, Zhang B et al (2013) Distinct alpha-synuclein strains differentially promote tau inclusions in neurons. Cell 154:103–117. https://doi.org/10.1016/j.cell.2013.05.057

    Article  CAS  PubMed  Google Scholar 

  24. Healy DG, Falchi M, O'Sullivan SS, Bonifati V, Durr A, Bressman Set al (2008) Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson's disease: a case-control study. Lancet Neurol 7:583–590. https://doi.org/10.1016/S1474-4422(08)70117-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Henderson MX, Cornblath EJ, Darwich A, Zhang B, Brown H, Gathagan RJ et al (2019) Spread of alpha-synuclein pathology through the brain connectome is modulated by selective vulnerability and predicted by network analysis. Nat Neurosci 22:1248–1257. https://doi.org/10.1038/s41593-019-0457-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Holth JK, Fritschi SK, Wang C, Pedersen NP, Cirrito JR, Mahan TE et al (2019) The sleep-wake cycle regulates brain interstitial fluid tau in mice and CSF tau in humans. Science 363:880–884. https://doi.org/10.1126/science.aav2546

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Humpel C (2015) Organotypic brain slice cultures: a review. Neuroscience 305:86–98. https://doi.org/10.1016/j.neuroscience.2015.07.086

    Article  CAS  PubMed  Google Scholar 

  28. Irwin DJ, Lee VM, Trojanowski JQ (2013) Parkinson's disease dementia: convergence of alpha-synuclein, tau and amyloid-beta pathologies. Nat Rev Neurosci 14:626–636. https://doi.org/10.1038/nrn3549

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Karpowicz RJ Jr, Haney CM, Mihaila TS, Sandler RM, Petersson EJ, Lee VM (2017) Selective imaging of internalized proteopathic alpha-synuclein seeds in primary neurons reveals mechanistic insight into transmission of synucleinopathies. J Biol Chem 292:13482–13497. https://doi.org/10.1074/jbc.M117.780296

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Lesage S, Drouet V, Majounie E, Deramecourt V, Jacoupy M, Nicolas A et al (2016) Loss of VPS13C function in autosomal-recessive parkinsonism causes mitochondrial dysfunction and increases PINK1/parkin-dependent mitophagy. Am J Hum Genet 98:500–513. https://doi.org/10.1016/j.ajhg.2016.01.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Loria F, Vargas JY, Bousset L, Syan S, Salles A, Melki R et al (2017) alpha-Synuclein transfer between neurons and astrocytes indicates that astrocytes play a role in degradation rather than in spreading. Acta Neuropathol 134:789–808. https://doi.org/10.1007/s00401-017-1746-2

    Article  CAS  PubMed  Google Scholar 

  32. Luk KC, Kehm V, Carroll J, Zhang B, O'Brien P, Trojanowski JQ et al (2012) Pathological alpha-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice. Science 338:949–953. https://doi.org/10.1126/science.1227157

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Luk KC, Kehm VM, Zhang B, O'Brien P, Trojanowski JQ, Lee VM (2012) Intracerebral inoculation of pathological alpha-synuclein initiates a rapidly progressive neurodegenerative alpha-synucleinopathy in mice. J Exp Med 209:975–986. https://doi.org/10.1084/jem.20112457

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Luna E, Decker SC, Riddle DM, Caputo A, Zhang B, Cole T et al (2018) Differential alpha-synuclein expression contributes to selective vulnerability of hippocampal neuron subpopulations to fibril-induced toxicity. Acta Neuropathol 135:855–875. https://doi.org/10.1007/s00401-018-1829-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Matikainen-Ankney BA, Kezunovic N, Mesias RE, Tian Y, Williams FM, Huntley GW et al (2016) Altered development of synapse structure and function in striatum caused by parkinson's disease-linked LRRK2-G2019S mutation. J Neurosci 36:7128–7141. https://doi.org/10.1523/JNEUROSCI.3314-15.2016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Messing L, Decker JM, Joseph M, Mandelkow E, Mandelkow EM (2013) Cascade of tau toxicity in inducible hippocampal brain slices and prevention by aggregation inhibitors. Neurobiol Aging 34:1343–1354. https://doi.org/10.1016/j.neurobiolaging.2012.10.024

    Article  CAS  PubMed  Google Scholar 

  37. Novotny R, Langer F, Mahler J, Skodras A, Vlachos A, Wegenast-Braun BM et al (2016) Conversion of synthetic abeta to in vivo active seeds and amyloid plaque formation in a hippocampal slice culture model. J Neurosci 36:5084–5093. https://doi.org/10.1523/JNEUROSCI.0258-16.2016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Oakley H, Cole SL, Logan S, Maus E, Shao P, Craft J et al (2006) Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer's disease mutations: potential factors in amyloid plaque formation. J Neurosci 26:10129–10140. https://doi.org/10.1523/JNEUROSCI.1202-06.2006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Opitz-Araya X, Barria A (2011) Organotypic hippocampal slice cultures. J Vis Exp. https://doi.org/10.3791/2462

    Article  PubMed  PubMed Central  Google Scholar 

  40. Pang SY, Ho PW, Liu HF, Leung CT, Li L, Chang EES et al (2019) The interplay of aging, genetics and environmental factors in the pathogenesis of Parkinson's disease. Transl Neurodegener 8:23. https://doi.org/10.1186/s40035-019-0165-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Pankratz N, Foroud T (2007) Genetics of Parkinson disease. Genet Med 9:801–811. https://doi.org/10.1097/gim.0b013e31815bf97c

    Article  PubMed  Google Scholar 

  42. Perier C, Vila M (2012) Mitochondrial biology and Parkinson's disease. Cold Spring Harb Perspect Med 2:a009332. https://doi.org/10.1101/cshperspect.a009332

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Remple MS, Bradenham CH, Kao CC, Charles PD, Neimat JS, Konrad PE (2011) Subthalamic nucleus neuronal firing rate increases with Parkinson's disease progression. Mov Disord 26:1657–1662. https://doi.org/10.1002/mds.23708

    Article  PubMed  PubMed Central  Google Scholar 

  44. Ren C, Ding Y, Wei S, Guan L, Zhang C, Ji Y et al (2019) G2019S variation in LRRK2: an ideal model for the study of Parkinson's disease? Front Hum Neurosci 13:306. https://doi.org/10.3389/fnhum.2019.00306

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Rodriguez MC, Obeso JA, Olanow CW (1998) Subthalamic nucleus-mediated excitotoxicity in Parkinson's disease: a target for neuroprotection. Ann Neurol 44:S175–188. https://doi.org/10.1002/ana.410440726

    Article  CAS  PubMed  Google Scholar 

  46. Rodriguez PC, Pereira DB, Borgkvist A, Wong MY, Barnard C, Sonders MS et al (2013) Fluorescent dopamine tracer resolves individual dopaminergic synapses and their activity in the brain. Proc Natl Acad Sci USA 110:870–875. https://doi.org/10.1073/pnas.1213569110

    Article  PubMed  Google Scholar 

  47. Sampathu DM, Giasson BI, Pawlyk AC, Trojanowski JQ, Lee VM (2003) Ubiquitination of alpha-synuclein is not required for formation of pathological inclusions in alpha-synucleinopathies. Am J Pathol 163:91–100. https://doi.org/10.1016/s0002-9440(10)63633-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Santa-Maria I, Diaz-Ruiz C, Ksiezak-Reding H, Chen A, Ho L, Wang J et al (2012) GSPE interferes with tau aggregation in vivo: implication for treating tauopathy. Neurobiol Aging 33:2072–2081. https://doi.org/10.1016/j.neurobiolaging.2011.09.027

    Article  CAS  PubMed  Google Scholar 

  49. Schatzle P, Kapitein LC, Hoogenraad CC (2016) Live imaging of microtubule dynamics in organotypic hippocampal slice cultures. Methods Cell Biol 131:107–126. https://doi.org/10.1016/bs.mcb.2015.06.006

    Article  PubMed  Google Scholar 

  50. Son AY, Biagioni MC, Kaminski D, Gurevich A, Stone B, Di Rocco A (2016) Parkinson's disease and cryptogenic epilepsy. Case Rep Neurol Med 2016:3745631. https://doi.org/10.1155/2016/3745631

    Article  PubMed  PubMed Central  Google Scholar 

  51. Spillantini MG, Crowther RA, Jakes R, Cairns NJ, Lantos PL, Goedert M (1998) Filamentous alpha-synuclein inclusions link multiple system atrophy with Parkinson's disease and dementia with Lewy bodies. Neurosci Lett 251:205–208. https://doi.org/10.1016/s0304-3940(98)00504-7

    Article  CAS  PubMed  Google Scholar 

  52. Spillantini MG, Goedert M (2016) Synucleinopathies: past, present and future. Neuropathol Appl Neurobiol 42:3–5. https://doi.org/10.1111/nan.12311

    Article  CAS  PubMed  Google Scholar 

  53. Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M (1997) Alpha-synuclein in Lewy bodies. Nature 388:839–840. https://doi.org/10.1038/42166

    Article  CAS  PubMed  Google Scholar 

  54. Stoppini L, Buchs PA, Muller D (1991) A simple method for organotypic cultures of nervous tissue. J Neurosci Methods 37:173–182. https://doi.org/10.1016/0165-0270(91)90128-m

    Article  CAS  PubMed  Google Scholar 

  55. Su X, Fischer DL, Li X, Bankiewicz K, Sortwell CE, Federoff HJ (2017) Alpha-synuclein mRNA is not increased in sporadic PD and alpha-synuclein accumulation does not block GDNF signaling in Parkinson's disease and disease models. Mol Ther 25:2231–2235. https://doi.org/10.1016/j.ymthe.2017.04.018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Surmeier DJ, Obeso JA, Halliday GM (2017) Selective neuronal vulnerability in Parkinson disease. Nat Rev Neurosci 18:101–113. https://doi.org/10.1038/nrn.2016.178

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Thakur P, Breger LS, Lundblad M, Wan OW, Mattsson B, Luk KC et al (2017) Modeling Parkinson's disease pathology by combination of fibril seeds and alpha-synuclein overexpression in the rat brain. Proc Natl Acad Sci USA 114:E8284–E8293. https://doi.org/10.1073/pnas.1710442114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Uemura N, Uemura MT, Lo A, Bassil F, Zhang B, Luk KC et al (2019) Slow progressive accumulation of oligodendroglial alpha-synuclein (alpha-Syn) pathology in synthetic alpha-syn fibril-induced mouse models of synucleinopathy. J Neuropathol Exp Neurol 78:877–890. https://doi.org/10.1093/jnen/nlz070

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Velasco S, Kedaigle AJ, Simmons SK, Nash A, Rocha M, Quadrato G et al (2019) Individual brain organoids reproducibly form cell diversity of the human cerebral cortex. Nature 570:523–527. https://doi.org/10.1038/s41586-019-1289-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Volpicelli-Daley LA, Luk KC, Lee VM (2014) Addition of exogenous alpha-synuclein preformed fibrils to primary neuronal cultures to seed recruitment of endogenous alpha-synuclein to Lewy body and Lewy neurite-like aggregates. Nat Protoc 9:2135–2146. https://doi.org/10.1038/nprot.2014.143

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Volpicelli-Daley LA, Luk KC, Patel TP, Tanik SA, Riddle DM, Stieber A et al (2011) Exogenous alpha-synuclein fibrils induce Lewy body pathology leading to synaptic dysfunction and neuron death. Neuron 72:57–71. https://doi.org/10.1016/j.neuron.2011.08.033

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Wang C, Kang X, Zhou L, Chai Z, Wu Q, Huang R et al (2018) Synaptotagmin-11 is a critical mediator of parkin-linked neurotoxicity and Parkinson's disease-like pathology. Nat Commun 9:81. https://doi.org/10.1038/s41467-017-02593-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Wang Y, Wu Q, Hu M, Liu B, Chai Z, Huang R et al (2017) Ligand- and voltage-gated Ca(2+) channels differentially regulate the mode of vesicular neuropeptide release in mammalian sensory neurons. Sci Signal 10:484. https://doi.org/10.1126/scisignal.aal1683

    Article  CAS  Google Scholar 

  64. Waxman EA, Giasson BI (2008) Specificity and regulation of casein kinase-mediated phosphorylation of alpha-synuclein. J Neuropathol Exp Neurol 67:402–416. https://doi.org/10.1097/NEN.0b013e31816fc995

    Article  CAS  PubMed  Google Scholar 

  65. Wu JW, Hussaini SA, Bastille IM, Rodriguez GA, Mrejeru A, Rilett K et al (2016) Neuronal activity enhances tau propagation and tau pathology in vivo. Nat Neurosci 19:1085–1092. https://doi.org/10.1038/nn.4328

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Wu Q, Takano H, Riddle DM, Trojanowski JQ, Coulter DA, Lee VM (2019) alpha-Synuclein (alphaSyn) preformed fibrils induce endogenous alphaSyn aggregation, compromise synaptic activity and enhance synapse loss in cultured excitatory hippocampal neurons. J Neurosci 39:5080–5094. https://doi.org/10.1523/JNEUROSCI.0060-19.2019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Yamada K, Holth JK, Liao F, Stewart FR, Mahan TE, Jiang H et al (2014) Neuronal activity regulates extracellular tau in vivo. J Exp Med 211:387–393. https://doi.org/10.1084/jem.20131685

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Yamada K, Iwatsubo T (2018) Extracellular alpha-synuclein levels are regulated by neuronal activity. Mol Neurodegen 13:9. https://doi.org/10.1186/s13024-018-0241-0

    Article  CAS  Google Scholar 

  69. Yu H, Sternad D, Corcos DM, Vaillancourt DE (2007) Role of hyperactive cerebellum and motor cortex in Parkinson's disease. Neuroimage 35:222–233. https://doi.org/10.1016/j.neuroimage.2006.11.047

    Article  PubMed  Google Scholar 

  70. Yuan P, Grutzendler J (2016) Attenuation of beta-amyloid deposition and neurotoxicity by chemogenetic modulation of neural activity. J Neurosci 36:632–641. https://doi.org/10.1523/JNEUROSCI.2531-15.2016

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Dr. Kurt R. Brunden for reading and editing of this manuscript. We thank Drs. Douglas A Coulter (Children’s hospital of Philadelphia) and Hajime Takano (Children’s hospital of Philadelphia) for valuable discussion and technical support. We thank S. Leight and T. Schuck for technical assistance. We thank Drs. A. Caputo for providing SGKI mice and M. X. Henderson for providing LRRK2 G2019S KI mice and discussion. We thank D. M. Riddle for primary hippocampal neuron cultures. We thank Dr. S. Xie for help with statistical analysis.

Funding

This work was supported by NIH/NIA U19 Center grant (AG062418), the Jeff and Anne Keefer Fund, and the Neurodegenerative Disease Research Fund.

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  1. Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104-4283, USA

    Qihui Wu, Muhammad A. Shaikh, Emily S. Meymand, Bin Zhang, Kelvin C. Luk, John Q. Trojanowski & Virginia M.-Y. Lee

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QW designed the studies and generated the data along with MAS. QW analyzed and interpreted all the results. BZ and ESM performed mouse brain injection surgeries. KCL, VM-YL, and JQT participated in discussion of results and design of some experiments, as well as in editing of the manuscript. QW and VM-YL wrote the manuscript, and all coauthors read and approved the manuscript. VM-YL supervised the study.

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Correspondence to Virginia M.-Y. Lee.

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Wu, Q., Shaikh, M.A., Meymand, E.S. et al. Neuronal activity modulates alpha-synuclein aggregation and spreading in organotypic brain slice cultures and in vivo. Acta Neuropathol 140, 831–849 (2020). https://doi.org/10.1007/s00401-020-02227-6

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