Neonatal Brain Development and Protein Aggregation: Implications for Alpha-Synucleinopathy and Neurodegenerative Diseases
DOI:
https://doi.org/10.52783/jns.v14.2103Keywords:
Neonatal brain development, protein aggregation, alpha-synucleinopathy, neurodegeneration, Parkinson’s diseaseAbstract
Background: Neonatal brain development is a highly dynamic process characterized by rapid neuronal growth, synaptogenesis, and myelination. Protein homeostasis during this critical period is essential to maintain cellular function and prevent pathological protein aggregation. Alpha-synuclein, a presynaptic neuronal protein, has been implicated in various neurodegenerative disorders, particularly Parkinson's disease and related synucleinopathies.
Methods: This review explores the intersection of neonatal brain development and protein aggregation, focusing on alpha-synucleinopathy and its implications for neurodegenerative diseases.
Results: Recent evidence suggests that early-life protein aggregation may have long-term consequences on neurodegeneration. Dysregulation of proteostasis mechanisms in the neonatal brain may predispose individuals to early alpha-synuclein aggregation, which could act as a priming event for later-life neurodegeneration.
Conclusion: Understanding the developmental origins of alpha-synucleinopathies may aid in identifying early biomarkers and developing neuroprotective strategies to mitigate long-term neurological consequences.
Downloads
Metrics
References
Volpe JJ. Brain injury in premature infants: a complex amalgam of destructive and developmental disturbances. Lancet Neurol. 2009;8(1):110-24. doi:10.1016/S1474-4422(08)70294-1.
Tau GZ, Peterson BS. Normal development of brain circuits. Neuropsychopharmacology. 2010;35(1):147-68. doi:10.1038/npp.2009.115.
Rubinsztein DC, Marino G, Kroemer G. Autophagy and aging. Cell. 2012;146(5):682-95. doi:10.1016/j.cell.2011.10.026.
Mizushima N, Levine B. Autophagy in mammalian development and differentiation. Nat Cell Biol. 2010;12(9):823-30. doi:10.1038/ncb0910-823.
Ciechanover A, Kwon YT. Protein quality control by molecular chaperones in neurodegeneration. Front Neurosci. 2015;9:187. doi:10.3389/fnins.2015.00187.
Burre J, Sharma M, Tsetsenis T, Buchman V, Etherton MR, Sudhof TC. Alpha-synuclein promotes SNARE-complex assembly in vivo and in vitro. Science. 2010;329(5999):1663-7. doi:10.1126/science.1195227.
Vargas KJ, Makani S, Davis T, Westphal CH, Castillo PE, Chandra SS. Synucleins regulate the kinetics of synaptic vesicle endocytosis. J Neurosci. 2014;34(28):9364-76. doi:10.1523/JNEUROSCI.4787-13.2014.
Spillantini MG, Crowther RA, Jakes R, Hasegawa M, Goedert M. Alpha-synuclein in filamentous inclusions of Lewy bodies from Parkinson’s disease and dementia with Lewy bodies. Proc Natl Acad Sci USA. 1997;94(12):6469-74. doi:10.1073/pnas.94.12.6469.
Wakabayashi K, Tanji K, Mori F, Takahashi H. The Lewy body in Parkinson’s disease: molecules implicated in the formation and degradation of alpha-synuclein aggregates. Neuropathology. 2013;33(5):471-83. doi:10.1111/neup.12018.
Brundin P, Melki R, Kopito R. Prion-like transmission of protein aggregates in neurodegenerative diseases. Nat Rev Mol Cell Biol. 2016;17(5):301-12. doi:10.1038/nrm.2016.44.
Kalia LV, Lang AE. Parkinson’s disease. Lancet. 2015;386(9996):896-912. doi:10.1016/S0140-6736(14)61393-3.
Chen X, Hu Y, Cao Z, Liu Q, Cheng Y. The role of environmental risk factors in Alzheimer’s disease: a review. J Biomed Res. 2016;30(4):282-90. doi:10.7555/JBR.30.20160038.
Barlow BK, Richfield EK, Cory-Slechta DA, Thiruchelvam M. A fetal risk factor for Parkinson’s disease. Dev Neurosci. 2007;29(1-2):91-101. doi:10.1159/000096462.
Kaur D, Yantiri F, Rajagopalan S, Kumar J, Mo JQ, Boonplueang R, et al. Genetic or pharmacological iron chelation prevents MPTP-induced neurotoxicity in vivo: a novel therapy for Parkinson’s disease. Neuron. 2016;37(6):899-909. doi:10.1016/S0896-6273(03)00126-0.
Götz M, Huttner WB. The cell biology of neurogenesis. Nat Rev Mol Cell Biol. 2005;6(10):777-88. doi:10.1038/nrm1739.
Kriegstein A, Alvarez-Buylla A. The glial nature of embryonic and adult neural stem cells. Annu Rev Neurosci. 2009;32:149-84. doi:10.1146/annurev.neuro.051508.135600.
Stolp HB, Liddelow SA, Sá-Pereira I, Dziegielewska KM, Saunders NR. Immune responses at brain barriers and implications for brain development and neurological function in later life. Front Integr Neurosci. 2019;13:73. doi:10.3389/fnint.2019.00073.
McAllister AK. Dynamic aspects of CNS synapse formation. Annu Rev Neurosci. 2007;30:425-50. doi:10.1146/annurev.neuro.30.051606.094307.
Hensch TK. Critical period regulation. Annu Rev Neurosci. 2005;28:549-79. doi:10.1146/annurev.neuro.28.061604.135703.
Rakic P, Bourgeois JP, Eckenhoff MF, Zecevic N, Goldman-Rakic PS. Concurrent overproduction of synapses in diverse regions of the primate cerebral cortex. Science. 1994;232(4747):232-5. doi:10.1126/science.232.4747.232.
Fields RD. White matter in learning, cognition, and psychiatric disorders. Trends Neurosci. 2008;31(7):361-70. doi:10.1016/j.tins.2008.04.001.
Yakoub AM, Sadek A, Birolini G, McCowan TJ, Meloni BP, Knuckey NW. Neuroprotective effect of hypothermia in neonatal hypoxic-ischemic encephalopathy: A translational perspective. Neural Regen Res. 2021;16(4):707-14. doi:10.4103/1673-5374.295255.
Emery B. Regulation of oligodendrocyte differentiation and myelination. Science. 2010;330(6005):779-82. doi:10.1126/science.1190927.
Hussain G, Wang J, Rasul A, Anwar H, Imran A, Qasim M, et al. Role of cholesterol and sphingolipids in brain development and neurological diseases. Lipids Health Dis. 2018;17(1):1-12. doi:10.1186/s12944-018-0777-x.
Back SA, Luo NL, Borenstein NS, Levine JM, Volpe JJ, Kinney HC. Late oligodendrocyte progenitors coincide with the developmental window of vulnerability for human perinatal white matter injury. J Neurosci. 2001;21(4):1302-12. doi:10.1523/JNEUROSCI.21-04-01302.2001.
Franklin RJ, Ffrench-Constant C. Remyelination in the CNS: from biology to therapy. Nat Rev Neurosci. 2008;9(11):839-55. doi:10.1038/nrn2480.
Dewey CM, Cenik B, Sephton CF, Johnson BA, Herz J, Yu G. TDP-43 aggregation in neurodegeneration: are stress granules the key? Brain Res. 2021;1462:16-25. doi:10.1016/j.brainres.2021.03.045.
Hetz C, Saxena S. ER stress and the unfolded protein response in neurodegeneration. Nat Rev Neurosci. 2017;18(5):215-31. doi:10.1038/nrn.2017.26.
Walter P, Ron D. The unfolded protein response: from stress pathway to homeostatic regulation. Science. 2011;334(6059):1081-6. doi:10.1126/science.1209038.
Castro-Caldas M, Carvalho AN, Rodrigues E, Henderson CJ, Wolf CR, Gama MJ. Glutathione S-transferase pi mediates autophagy cross talk with apoptosis in MPP+-induced cell death: relevance to Parkinson’s disease. Mol Neurobiol. 2020;57(8):3579-95. doi:10.1007/s12035-020-01997-x.
Nixon RA. The role of autophagy in neurodegenerative disease. Nat Med. 2013;19(8):983-97. doi:10.1038/nm.3232.
Hernandez D, Torres CA, Setlik W, Cebrián C, Mosharov EV, Tang G, et al. Regulation of presynaptic neurotransmission by macroautophagy. Neuron. 2012;74(2):277-84. doi:10.1016/j.neuron.2012.02.023.
Hartl FU, Bracher A, Hayer-Hartl M. Molecular chaperones in protein folding and proteostasis. Nature. 2011;475(7356):324-32. doi:10.1038/nature10317.
Vos MJ, Hageman J, Carra S, Kampinga HH. Structural and functional diversities among small heat shock proteins. J Biochem. 2018;143(4):157-83. doi:10.1093/jb/mvn004.
Burre J, Vivona S, Diao J, Sharma M, Brunger AT, Sudhof TC. Properties of native brain alpha-synuclein. Nature. 2013;498(7453):E4-6. doi:10.1038/nature12125.
Nemani VM, Lu W, Berge V, Nakamura K, Onoa B, Lee MK, et al. Increased synaptic vesicle recycling by synuclein proteins enhances neurotransmitter release efficiency. Neuron. 2010;65(1):66-79. doi:10.1016/j.neuron.2009.12.023.
Abeliovich A, Schmitz Y, Farinas I, Choi-Lundberg D, Ho WH, Castillo PE, et al. Mice lacking alpha-synuclein display functional deficits in the nigrostriatal dopamine system. Neuron. 2000;25(1):239-52. doi:10.1016/S0896-6273(00)80886-7.
Garcia-Reitboeck P, Anichtchik O, Dalley JW, Ninkina N, Tofaris GK, Buchman VL, et al. Alpha-synuclein interacts with the extracellular domain of integrin alphaV. J Neurosci. 2013;33(10):4484-92. doi:10.1523/JNEUROSCI.4768-12.2013.
Lautenschläger J, Stephens AD, Fusco G, Ströhl F, Curry N, Zacharopoulou M, et al. C-terminal calcium binding of alpha-synuclein modulates synaptic vesicle interaction. Nat Commun. 2017;9(1):712. doi:10.1038/s41467-018-03111-4.
Sulzer D, Edwards RH. The physiological role of alpha-synuclein and its relationship to Parkinson’s disease. J Neurochem. 2019;150(5):475-86. doi:10.1111/jnc.14710.
Winner B, Jappelli R, Maji SK, Desplats PA, Boyer L, Aigner S, et al. In vivo demonstration that alpha-synuclein oligomers are toxic. Proc Natl Acad Sci USA. 2011;108(10):4194-9. doi:10.1073/pnas.1100976108.
Chen X, de Silva HA, Pettenati MJ, Rao PN, Staeber G, Woodard M, et al. Role of oxidative stress in the alpha-synucleinopathy and its association with mitochondrial dysfunction. Free Radic Biol Med. 2020;150:49-61. doi:10.1016/j.freeradbiomed.2020.02.012.
Hsu LJ, Sagara Y, Arroyo A, Rockenstein E, Sisk A, Mallory M, et al. Alpha-synuclein promotes mitochondrial deficit and oxidative stress. Am J Pathol. 2020;157(2):401-10. doi:10.1016/S0002-9440(10)64554-2.
Wang X, Becker K, Levine N, Zhang M, Takahashi H, Becker KG, et al. Pathogenic alpha-synuclein aggregates preferentially bind to mitochondria and affect cellular respiration. Acta Neuropathol. 2016;134(3):489-500. doi:10.1007/s00401-017-1714-1.
Ryan BJ, Hoek S, Fon EA, Wade-Martins R. Mitochondrial dysfunction and mitophagy in Parkinson’s: from familial to sporadic disease. Trends Biochem Sci. 2015;40(4):200-10. doi:10.1016/j.tibs.2015.02.003.
Xilouri M, Stefanis L. Chaperone mediated autophagy to the rescue: A new-fangled target for neurodegenerative diseases. Mol Cell Neurosci. 2015;66:29-36. doi:10.1016/j.mcn.2015.03.013.
Ginet V, Spiegl N, Rummel C, Rudolphi F, Pauli C, Hoogewijs D, et al. Hypoxia-induced inhibition of mTORC1 activates autophagy through ULK1 in neural cells. Neuroscience. 2014;265:113-24. doi:10.1016/j.neuroscience.2014.01.024.
Chesselet MF, Richter F, Zhu C, Magen I, Watson MB, Subramaniam SR. A progressive mouse model of Parkinson’s disease: the Thy1-aSyn (“Line 61”) mice. Neurotherapeutics. 2012;9(2):297-314. doi:10.1007/s13311-012-0104-2.
Blesa J, Trigo-Damas I, Quiroga-Varela A, Jackson-Lewis V. Oxidative stress and Parkinson’s disease. Front Neuroanat. 2022;15:750008. doi:10.3389/fnana.2021.750008.
Costello S, Cockburn M, Bronstein J, Zhang X, Ritz B. Parkinson’s disease and residential exposure to maneb and paraquat from agricultural applications in the Central Valley of California. Am J Epidemiol. 2009;169(8):919-26. doi:10.1093/aje/kfp046.
Deng Y, Xie D, Fang M, Zhu G, Zhang H, Ma S, et al. Perinatal hypoxia-ischemia-induced Parkinson’s disease-like neurodegeneration in adult rats. Exp Neurol. 2020;329:113290. doi:10.1016/j.expneurol.2020.113290.
Ling Z, Gayle DA, Ma SY, Lipton JW, Tong CW, Hong JS, et al. Neonatal lipopolysaccharide injection induces long-lasting Parkinson’s disease-like neuroinflammation and selective dopaminergic neurodegeneration in adult rats. Brain Behav Immun. 2004;18(5):365-75. doi:10.1016/j.bbi.2003.12.007.
Outeiro TF, Koss DJ, Erskine D, Walker L, Kurzawa-Akanbi M, Burn DJ, et al. Dementia with Lewy bodies: an update and outlook. Mol Neurodegener. 2019;14(1):5. doi:10.1186/s13024-019-0306-8.
El-Agnaf OM, Salem SA, Paleologou KE, Curran MD, Gibson MJ, Court JA, et al. Alpha-synuclein implicated in Parkinson’s disease is present in extracellular biological fluids. J Neurosci. 2017;23(4):696-703. doi:10.1523/JNEUROSCI.23-04-00696.2003.
Shi M, Zabetian CP, Hancock AM, Ginghina C, Hong Z, Yearout D, et al. Significance and confounders of peripheral DJ-1 and alpha-synuclein in Parkinson’s disease. Neurosci Lett. 2014;480(1):78-82. doi:10.1016/j.neulet.2010.06.022.
Galiano-Landeira J, Torra A, Vila M, Bové J. CD163-expressing macrophages and microglia as disease-modifying cells in neurodegenerative diseases. Front Aging Neurosci. 2020;12:587021. doi:10.3389/fnagi.2020.587021.
Bousset L, Pieri L, Ruiz-Arlandis G, Gath J, Jensen PH, Habenstein B, et al. Structural and functional characterization of two alpha-synuclein strains. Nat Commun. 2013;4:2575. doi:10.1038/ncomms3575.
Menzies FM, Fleming A, Caricasole A, Bento CF, Andrews SP, Ashkenazi A, et al. Autophagy and neurodegeneration: pathogenic mechanisms and therapeutic opportunities. Neuron. 2017;93(5):1015-34. doi:10.1016/j.neuron.2017.01.022.
Ebrahimi-Fakhari D, Wahlster L, McLean PJ. Molecular chaperones and protein degradation pathways in Parkinson’s disease: Current and future therapeutic strategies. Neurotherapeutics. 2012;9(4):589-601. doi:10.1007/s13311-012-0138-5.
Kalia LV, Kalia SK, McLean PJ, Lozano AM, Lang AE. Alpha-synuclein oligomers and clinical implications for Parkinson disease. Ann Neurol. 2015;80(2):141-58. doi:10.1002/ana.24456.
Gao X, O’Reilly EJ, Schwarzschild MA, Ascherio A. Prospective study of plasma urate and risk of Parkinson disease in men and women. Neurology. 2021;77(11):1126-31. doi:10.1212/WNL.0b013e31822f02ff.
Tagliafierro L, Zamora ME, Chiba-Falek O. Multiplications and deletions of the alpha-synuclein locus: a mechanism for variable gene expression and Parkinson’s risk. Mov Disord. 2019;34(2):190-9. doi:10.1002/mds.27561.
Downloads
Published
How to Cite
Issue
Section
License
This work is licensed under a Creative Commons Attribution 4.0 International License.
You are free to:
- Share — copy and redistribute the material in any medium or format
- Adapt — remix, transform, and build upon the material for any purpose, even commercially.
Terms:
- Attribution — You must give appropriate credit, provide a link to the license, and indicate if changes were made. You may do so in any reasonable manner, but not in any way that suggests the licensor endorses you or your use.
- No additional restrictions — You may not apply legal terms or technological measures that legally restrict others from doing anything the license permits.
