A role for α-Synuclein in axon growth and its implications in corticostriatal glutamatergic plasticity in Parkinson’s disease
Abstract Background α-Synuclein (α-Syn) is a protein implicated in the pathogenesis of Parkinson’s disease (PD). α-Syn has been shown to associate with membranes and bind acidic phospholipids. However, the physiological importance of these associations to the integrity of axons is not fully clear. M...
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doaj-23d231e5775545c5a0206e97aa70d5ad2020-11-25T02:29:21ZengBMCMolecular Neurodegeneration1750-13262020-03-0115112110.1186/s13024-020-00370-yA role for α-Synuclein in axon growth and its implications in corticostriatal glutamatergic plasticity in Parkinson’s diseaseMeir Schechter0Jessica Grigoletto1Suaad Abd-Elhadi2Hava Glickstein3Alexander Friedman4Geidy E. Serrano5Thomas G. Beach6Ronit Sharon7Department of Biochemistry and Molecular Biology, IMRIC, The Hebrew University-Hadassah Medical SchoolDepartment of Biochemistry and Molecular Biology, IMRIC, The Hebrew University-Hadassah Medical SchoolDepartment of Biochemistry and Molecular Biology, IMRIC, The Hebrew University-Hadassah Medical SchoolElectron Microscopy Unit, The Hebrew University-Hadassah Medical SchoolMcGovern Institute for Brain Research and Department of Brain and Cognitive Sciences, Massachusetts Institute of TechnologyBanner Sun Health Research InstituteBanner Sun Health Research InstituteDepartment of Biochemistry and Molecular Biology, IMRIC, The Hebrew University-Hadassah Medical SchoolAbstract Background α-Synuclein (α-Syn) is a protein implicated in the pathogenesis of Parkinson’s disease (PD). α-Syn has been shown to associate with membranes and bind acidic phospholipids. However, the physiological importance of these associations to the integrity of axons is not fully clear. Methods Biochemical, immunohistochemical and ultrastructural analyses in cultured neurons, transgenic mouse brains, PD and control human brains. Results We analyzed the ultrastructure of cross-sectioned axons localized to white matter tracts (WMTs), within the dorsal striatum of old and symptomatic α-Syn transgenic mouse brains. The analysis indicated a higher density of axons of thinner diameter. Our findings in cultured cortical neurons indicate a role for α-Syn in elongation of the main axon and its collaterals, resulting in enhanced axonal arborization. We show that α-Syn effect to enhance axonal outgrowth is mediated through its activity to regulate membrane levels of the acidic phosphatidylinositol 4,5-bisphosphate (PI4,5P2). Moreover, our findings link α-Syn- enhanced axonal growth with evidence for axonal injury. In relevance to disease mechanisms, we detect in human brains evidence for a higher degree of corticostriatal glutamatergic plasticity within WMTs at early stages of PD. However, at later PD stages, the respective WMTs in the caudate are degenerated with accumulation of Lewy pathology. Conclusions Our results show that through regulating PI4,5P2 levels, α-Syn acts to elongate the main axon and collaterals, resulting in a higher density of axons in the striatal WMTs. Based on these results we suggest a role for α-Syn in compensating mechanisms, involving corticostriatal glutamatergic plasticity, taking place early in PD.http://link.springer.com/article/10.1186/s13024-020-00370-yParkinson’s diseaseCorticostriatal axonsα-SynucleinPhosphatidylinositol 4,5-bisphosphate (PI4,5P2)White matter tracts (WMTs)Axonal injury |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Meir Schechter Jessica Grigoletto Suaad Abd-Elhadi Hava Glickstein Alexander Friedman Geidy E. Serrano Thomas G. Beach Ronit Sharon |
spellingShingle |
Meir Schechter Jessica Grigoletto Suaad Abd-Elhadi Hava Glickstein Alexander Friedman Geidy E. Serrano Thomas G. Beach Ronit Sharon A role for α-Synuclein in axon growth and its implications in corticostriatal glutamatergic plasticity in Parkinson’s disease Molecular Neurodegeneration Parkinson’s disease Corticostriatal axons α-Synuclein Phosphatidylinositol 4,5-bisphosphate (PI4,5P2) White matter tracts (WMTs) Axonal injury |
author_facet |
Meir Schechter Jessica Grigoletto Suaad Abd-Elhadi Hava Glickstein Alexander Friedman Geidy E. Serrano Thomas G. Beach Ronit Sharon |
author_sort |
Meir Schechter |
title |
A role for α-Synuclein in axon growth and its implications in corticostriatal glutamatergic plasticity in Parkinson’s disease |
title_short |
A role for α-Synuclein in axon growth and its implications in corticostriatal glutamatergic plasticity in Parkinson’s disease |
title_full |
A role for α-Synuclein in axon growth and its implications in corticostriatal glutamatergic plasticity in Parkinson’s disease |
title_fullStr |
A role for α-Synuclein in axon growth and its implications in corticostriatal glutamatergic plasticity in Parkinson’s disease |
title_full_unstemmed |
A role for α-Synuclein in axon growth and its implications in corticostriatal glutamatergic plasticity in Parkinson’s disease |
title_sort |
role for α-synuclein in axon growth and its implications in corticostriatal glutamatergic plasticity in parkinson’s disease |
publisher |
BMC |
series |
Molecular Neurodegeneration |
issn |
1750-1326 |
publishDate |
2020-03-01 |
description |
Abstract Background α-Synuclein (α-Syn) is a protein implicated in the pathogenesis of Parkinson’s disease (PD). α-Syn has been shown to associate with membranes and bind acidic phospholipids. However, the physiological importance of these associations to the integrity of axons is not fully clear. Methods Biochemical, immunohistochemical and ultrastructural analyses in cultured neurons, transgenic mouse brains, PD and control human brains. Results We analyzed the ultrastructure of cross-sectioned axons localized to white matter tracts (WMTs), within the dorsal striatum of old and symptomatic α-Syn transgenic mouse brains. The analysis indicated a higher density of axons of thinner diameter. Our findings in cultured cortical neurons indicate a role for α-Syn in elongation of the main axon and its collaterals, resulting in enhanced axonal arborization. We show that α-Syn effect to enhance axonal outgrowth is mediated through its activity to regulate membrane levels of the acidic phosphatidylinositol 4,5-bisphosphate (PI4,5P2). Moreover, our findings link α-Syn- enhanced axonal growth with evidence for axonal injury. In relevance to disease mechanisms, we detect in human brains evidence for a higher degree of corticostriatal glutamatergic plasticity within WMTs at early stages of PD. However, at later PD stages, the respective WMTs in the caudate are degenerated with accumulation of Lewy pathology. Conclusions Our results show that through regulating PI4,5P2 levels, α-Syn acts to elongate the main axon and collaterals, resulting in a higher density of axons in the striatal WMTs. Based on these results we suggest a role for α-Syn in compensating mechanisms, involving corticostriatal glutamatergic plasticity, taking place early in PD. |
topic |
Parkinson’s disease Corticostriatal axons α-Synuclein Phosphatidylinositol 4,5-bisphosphate (PI4,5P2) White matter tracts (WMTs) Axonal injury |
url |
http://link.springer.com/article/10.1186/s13024-020-00370-y |
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