Pathological Endogenous α-Synuclein Accumulation in Oligodendrocyte Precursor Cells Potentially Induces Inclusions in Multiple System Atrophy

Overview

Journal Stem Cell Reports

Publisher Cell Press

Specialty Cell Biology

Date 2018 Jan 17

PMID 29337114

Citations 45

Authors

Seiji Kaji

Takakuni Maki

Hisanori Kinoshita

Norihito Uemura

Takashi Ayaki

Yasuhiro Kawamoto

Takahiro Furuta

Makoto Urushitani

Masato Hasegawa

Yusuke Kinoshita

Yuichi Ono

Xiaobo Mao

Tran H Quach

Kazuhiro Iwai

Valina L Dawson

Ted M Dawson

Ryosuke Takahashi

Affiliations

Soon will be listed here.

Abstract

Glial cytoplasmic inclusions (GCIs), commonly observed as α-synuclein (α-syn)-positive aggregates within oligodendrocytes, are the pathological hallmark of multiple system atrophy. The origin of α-syn in GCIs is uncertain; there is little evidence of endogenous α-syn expression in oligodendrocyte lineage cells, oligodendrocyte precursor cells (OPCs), and mature oligodendrocytes (OLGs). Here, based on in vitro analysis using primary rat cell cultures, we elucidated that preformed fibrils (PFFs) generated from recombinant human α-syn trigger multimerization and an upsurge of endogenous α-syn in OPCs, which is attributable to insufficient autophagic proteolysis. RNA-seq analysis of OPCs revealed that α-syn PFFs interfered with the expression of proteins associated with neuromodulation and myelination. Furthermore, we detected cytoplasmic α-syn inclusions in OLGs through differentiation of OPCs pre-incubated with PFFs. Overall, our findings suggest the possibility of endogenous α-syn accumulation in OPCs that contributes to GCI formation and perturbation of neuronal/glial support in multiple system atrophy brains.

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References

Schwarz L, Goldbaum O, Bergmann M, Probst-Cousin S, Richter-Landsberg C . Involvement of macroautophagy in multiple system atrophy and protein aggregate formation in oligodendrocytes. J Mol Neurosci. 2012; 47(2):256-66. DOI: 10.1007/s12031-012-9733-5. View

Grice G, Nathan J . The recognition of ubiquitinated proteins by the proteasome. Cell Mol Life Sci. 2016; 73(18):3497-506. PMC: 4980412. DOI: 10.1007/s00018-016-2255-5. View

Fellner L, Jellinger K, Wenning G, Stefanova N . Glial dysfunction in the pathogenesis of α-synucleinopathies: emerging concepts. Acta Neuropathol. 2011; 121(6):675-93. PMC: 4730553. DOI: 10.1007/s00401-011-0833-z. View

Maki T, Takahashi Y, Miyamoto N, Liang A, Ihara M, Lo E . Adrenomedullin promotes differentiation of oligodendrocyte precursor cells into myelin-basic-protein expressing oligodendrocytes under pathological conditions in vitro. Stem Cell Res. 2015; 15(1):68-74. PMC: 4516627. DOI: 10.1016/j.scr.2015.05.001. View

Angot E, Steiner J, Hansen C, Li J, Brundin P . Are synucleinopathies prion-like disorders?. Lancet Neurol. 2010; 9(11):1128-38. DOI: 10.1016/S1474-4422(10)70213-1. View

Richter-Landsberg C, Gorath M, Trojanowski J, Lee V . alpha-synuclein is developmentally expressed in cultured rat brain oligodendrocytes. J Neurosci Res. 2000; 62(1):9-14. DOI: 10.1002/1097-4547(20001001)62:1<9::AID-JNR2>3.0.CO;2-U. View

Mutka A, Haapanen A, Kakela R, Lindfors M, Wright A, Inkinen T . Murine cathepsin D deficiency is associated with dysmyelination/myelin disruption and accumulation of cholesteryl esters in the brain. J Neurochem. 2009; 112(1):193-203. DOI: 10.1111/j.1471-4159.2009.06440.x. View

Levine J, Reynolds R, Fawcett J . The oligodendrocyte precursor cell in health and disease. Trends Neurosci. 2001; 24(1):39-47. DOI: 10.1016/s0166-2236(00)01691-x. View

Konno M, Hasegawa T, Baba T, Miura E, Sugeno N, Kikuchi A . Suppression of dynamin GTPase decreases α-synuclein uptake by neuronal and oligodendroglial cells: a potent therapeutic target for synucleinopathy. Mol Neurodegener. 2012; 7:38. PMC: 3479026. DOI: 10.1186/1750-1326-7-38. View

10.

Lee Y, Morrison B, Li Y, Lengacher S, Farah M, Hoffman P . Oligodendroglia metabolically support axons and contribute to neurodegeneration. Nature. 2012; 487(7408):443-8. PMC: 3408792. DOI: 10.1038/nature11314. View

11.

Masuda-Suzukake M, Nonaka T, Hosokawa M, Oikawa T, Arai T, Akiyama H . Prion-like spreading of pathological α-synuclein in brain. Brain. 2013; 136(Pt 4):1128-38. PMC: 3613715. DOI: 10.1093/brain/awt037. View

12.

Volpicelli-Daley L, Luk K, Patel T, Tanik S, Riddle D, Stieber A . Exogenous α-synuclein fibrils induce Lewy body pathology leading to synaptic dysfunction and neuron death. Neuron. 2011; 72(1):57-71. PMC: 3204802. DOI: 10.1016/j.neuron.2011.08.033. View

13.

Bae E, Yang N, Lee C, Kim S, Lee H, Lee S . Haploinsufficiency of cathepsin D leads to lysosomal dysfunction and promotes cell-to-cell transmission of α-synuclein aggregates. Cell Death Dis. 2015; 6:e1901. PMC: 4632307. DOI: 10.1038/cddis.2015.283. View

14.

Wenning G, Stefanova N, Jellinger K, Poewe W, Schlossmacher M . Multiple system atrophy: a primary oligodendrogliopathy. Ann Neurol. 2008; 64(3):239-46. DOI: 10.1002/ana.21465. View

15.

Wilkins A, Majed H, Layfield R, Compston A, Chandran S . Oligodendrocytes promote neuronal survival and axonal length by distinct intracellular mechanisms: a novel role for oligodendrocyte-derived glial cell line-derived neurotrophic factor. J Neurosci. 2003; 23(12):4967-74. PMC: 6741206. View

16.

Shults C, Rockenstein E, Crews L, Adame A, Mante M, Larrea G . Neurological and neurodegenerative alterations in a transgenic mouse model expressing human alpha-synuclein under oligodendrocyte promoter: implications for multiple system atrophy. J Neurosci. 2005; 25(46):10689-99. PMC: 6725840. DOI: 10.1523/JNEUROSCI.3527-05.2005. View

17.

Miller D, Johnson J, Solano S, Hollingsworth Z, Standaert D, Young A . Absence of alpha-synuclein mRNA expression in normal and multiple system atrophy oligodendroglia. J Neural Transm (Vienna). 2005; 112(12):1613-24. DOI: 10.1007/s00702-005-0378-1. View

18.

May V, Ettle B, Poehler A, Nuber S, Ubhi K, Rockenstein E . α-Synuclein impairs oligodendrocyte progenitor maturation in multiple system atrophy. Neurobiol Aging. 2014; 35(10):2357-68. PMC: 4087058. DOI: 10.1016/j.neurobiolaging.2014.02.028. View

19.

Djelloul M, Holmqvist S, Boza-Serrano A, Azevedo C, Yeung M, Goldwurm S . Alpha-Synuclein Expression in the Oligodendrocyte Lineage: an In Vitro and In Vivo Study Using Rodent and Human Models. Stem Cell Reports. 2015; 5(2):174-84. PMC: 4618831. DOI: 10.1016/j.stemcr.2015.07.002. View