Tauopathic changes in the striatum of A53T α-synuclein mutant mouse model of Parkinson's disease.

Tauopathic pathways lead to degenerative changes in Alzheimer's disease and there is evidence that they are also involved in the neurodegenerative pathology of Parkinson's disease [PD]. We have examined tauopathic changes in striatum of the α-synuclein (α-Syn) A53T mutant mouse. Elevated l...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Jonathan Wills, Joel Credle, Thomas Haggerty, Jae-Hoon Lee, Adam W Oaks, Anita Sidhu
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/096bf8750ce34565bb15c9bd65c13612
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:096bf8750ce34565bb15c9bd65c13612
record_format	dspace
spelling	oai:doaj.org-article:096bf8750ce34565bb15c9bd65c136122021-11-18T06:57:02ZTauopathic changes in the striatum of A53T α-synuclein mutant mouse model of Parkinson's disease.1932-620310.1371/journal.pone.0017953https://doaj.org/article/096bf8750ce34565bb15c9bd65c136122011-03-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21445308/?tool=EBIhttps://doaj.org/toc/1932-6203Tauopathic pathways lead to degenerative changes in Alzheimer's disease and there is evidence that they are also involved in the neurodegenerative pathology of Parkinson's disease [PD]. We have examined tauopathic changes in striatum of the α-synuclein (α-Syn) A53T mutant mouse. Elevated levels of α-Syn were observed in striatum of the adult A53T α-Syn mice. This was accompanied by increases in hyperphosphorylated Tau [p-Tau], phosphorylated at Ser202, Ser262 and Ser396/404, which are the same toxic sites also seen in Alzheimer's disease. There was an increase in active p-GSK-3β, hyperphosphorylated at Tyr216, a major and primary kinase known to phosphorylate Tau at multiple sites. The sites of hyperphosphorylation of Tau in the A53T mutant mice were similar to those seen in post-mortem striata from PD patients, attesting to their pathophysiological relevance. Increases in p-Tau were not due to alterations on protein phosphatases in either A53T mice or in human PD, suggesting lack of involvement of these proteins in tauopathy. Extraction of striata with Triton X-100 showed large increases in oligomeric forms of α-Syn suggesting that α-Syn had formed aggregates the mutant mice. In addition, increased levels of p-GSK-3β and pSer396/404 were also found associated with aggregated α-Syn. Differential solubilization to measure protein binding to cytoskeletal proteins demonstrated that p-Tau in the A53T mutant mouse were unbound to cytoskeletal proteins, consistent with dissociation of p-Tau from the microtubules upon hyperphosphorylation. Interestingly, α-Syn remained tightly bound to the cytoskeleton, while p-GSK-3β was seen in the cytoskeleton-free fractions. Immunohistochemical studies showed that α-Syn, pSer396/404 Tau and p-GSK-3β co-localized with one another and was aggregated and accumulated into large inclusion bodies, leading to cell death of Substantia nigral neurons. Together, these data demonstrate an elevated state of tauopathy in striata of the A53T α-Syn mutant mice, suggesting that tauopathy is a common feature of synucleinopathies.Jonathan WillsJoel CredleThomas HaggertyJae-Hoon LeeAdam W OaksAnita SidhuPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 6, Iss 3, p e17953 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Jonathan Wills Joel Credle Thomas Haggerty Jae-Hoon Lee Adam W Oaks Anita Sidhu Tauopathic changes in the striatum of A53T α-synuclein mutant mouse model of Parkinson's disease.
description	Tauopathic pathways lead to degenerative changes in Alzheimer's disease and there is evidence that they are also involved in the neurodegenerative pathology of Parkinson's disease [PD]. We have examined tauopathic changes in striatum of the α-synuclein (α-Syn) A53T mutant mouse. Elevated levels of α-Syn were observed in striatum of the adult A53T α-Syn mice. This was accompanied by increases in hyperphosphorylated Tau [p-Tau], phosphorylated at Ser202, Ser262 and Ser396/404, which are the same toxic sites also seen in Alzheimer's disease. There was an increase in active p-GSK-3β, hyperphosphorylated at Tyr216, a major and primary kinase known to phosphorylate Tau at multiple sites. The sites of hyperphosphorylation of Tau in the A53T mutant mice were similar to those seen in post-mortem striata from PD patients, attesting to their pathophysiological relevance. Increases in p-Tau were not due to alterations on protein phosphatases in either A53T mice or in human PD, suggesting lack of involvement of these proteins in tauopathy. Extraction of striata with Triton X-100 showed large increases in oligomeric forms of α-Syn suggesting that α-Syn had formed aggregates the mutant mice. In addition, increased levels of p-GSK-3β and pSer396/404 were also found associated with aggregated α-Syn. Differential solubilization to measure protein binding to cytoskeletal proteins demonstrated that p-Tau in the A53T mutant mouse were unbound to cytoskeletal proteins, consistent with dissociation of p-Tau from the microtubules upon hyperphosphorylation. Interestingly, α-Syn remained tightly bound to the cytoskeleton, while p-GSK-3β was seen in the cytoskeleton-free fractions. Immunohistochemical studies showed that α-Syn, pSer396/404 Tau and p-GSK-3β co-localized with one another and was aggregated and accumulated into large inclusion bodies, leading to cell death of Substantia nigral neurons. Together, these data demonstrate an elevated state of tauopathy in striata of the A53T α-Syn mutant mice, suggesting that tauopathy is a common feature of synucleinopathies.
format	article
author	Jonathan Wills Joel Credle Thomas Haggerty Jae-Hoon Lee Adam W Oaks Anita Sidhu
author_facet	Jonathan Wills Joel Credle Thomas Haggerty Jae-Hoon Lee Adam W Oaks Anita Sidhu
author_sort	Jonathan Wills
title	Tauopathic changes in the striatum of A53T α-synuclein mutant mouse model of Parkinson's disease.
title_short	Tauopathic changes in the striatum of A53T α-synuclein mutant mouse model of Parkinson's disease.
title_full	Tauopathic changes in the striatum of A53T α-synuclein mutant mouse model of Parkinson's disease.
title_fullStr	Tauopathic changes in the striatum of A53T α-synuclein mutant mouse model of Parkinson's disease.
title_full_unstemmed	Tauopathic changes in the striatum of A53T α-synuclein mutant mouse model of Parkinson's disease.
title_sort	tauopathic changes in the striatum of a53t α-synuclein mutant mouse model of parkinson's disease.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/096bf8750ce34565bb15c9bd65c13612
work_keys_str_mv	AT jonathanwills tauopathicchangesinthestriatumofa53tasynucleinmutantmousemodelofparkinsonsdisease AT joelcredle tauopathicchangesinthestriatumofa53tasynucleinmutantmousemodelofparkinsonsdisease AT thomashaggerty tauopathicchangesinthestriatumofa53tasynucleinmutantmousemodelofparkinsonsdisease AT jaehoonlee tauopathicchangesinthestriatumofa53tasynucleinmutantmousemodelofparkinsonsdisease AT adamwoaks tauopathicchangesinthestriatumofa53tasynucleinmutantmousemodelofparkinsonsdisease AT anitasidhu tauopathicchangesinthestriatumofa53tasynucleinmutantmousemodelofparkinsonsdisease
_version_	1718424148286373888

Tauopathic changes in the striatum of A53T α-synuclein mutant mouse model of Parkinson's disease.

Ejemplares similares