Identification of the Sites of Tau Hyperphosphorylation and Activation of Tau Kinases in Synucleinopathies and Alzheimer's Diseases

Valeriy Duka, Jae Hoon Lee, Joel Credle, Jonathan Wills, Adam Oaks, Ciaran Smolinsky, Ketul Shah, Deborah C Mash, Eliezer Masliah, Anita Sidhu

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

Objective:Most neurodegenerative diseases contain hyperphosphorylated Tau [p-Tau]. We examined for the first time epitopes at which Tau is hyperphosphorylated in Parkinson's disease, dementia with Lewy bodies and Alzheimer's disease, and also select Tau kinases.Methods:Postmortem frontal cortex from Parkinson's disease, dementia with Lewy bodies, Alzheimer's disease and striata from Parkinson's disease, were analyzed by immunoblots using commercially available antibodies against 20 different phospho-epitopes of Tau. Major Tau kinases were also screened. Results in diseased tissues were compared to nondiseased controls.Results:In Alzheimer's disease, Tau was hyperphosphorylated at all the 20 epitopes of p-Tau. In dementia with Lewy bodies, p-Tau formation occurred at 6 sites sharing 30% overlap with Alzheimer's disease, while in Parkinson's frontal cortex, an area which does not degenerate, Tau hyperphosphorylation was seen at just 3 epitopes, indicating 15% overlap with Alzheimer's disease. In Parkinson's disease striatum, an area which undergoes considerable neurodegeneration, Tau was hyperphosphorylated at 10 epitopes, sharing 50% overlap with Alzheimer's disease. Between frontal cortex of Parkinson's disease and dementia with Lewy bodies, there were only two p-Tau epitopes in common. In striata of Parkinson's disease, there were 3 clusters of Tau hyperphosphorylated at 3 contiguous sites, while two such clusters were detected in dementia with Lewy bodies; such clusters disrupt axonal transport of mitochondria, cause microtubule remodeling and result in cell death. p-GSK-3β, a major Tau kinase, was activated in all brain regions examined, except in dementia with Lewy bodies. Activation of other Tau kinases was seen in all brain regions, with no clear pattern of activation.Interpretation:Our studies suggest that the three neurodegenerative diseases each have a signature-specific profile of p-Tau formation which may be useful in understanding the genesis of the diseases and for the development of a panel of specific biomarkers.

Original languageEnglish
Article numbere75025
JournalPLoS One
Volume8
Issue number9
DOIs
StatePublished - Sep 20 2013

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Lewy Body Disease
dementia
Parkinson disease
Alzheimer disease
epitopes
Epitopes
Alzheimer Disease
Phosphotransferases
Chemical activation
Parkinson Disease
Frontal Lobe
neurodegenerative diseases
Neurodegenerative Diseases
Dementia
Glycogen Synthase Kinase 3
brain
Neurodegenerative diseases
Axonal Transport
Brain
Microtubules

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Identification of the Sites of Tau Hyperphosphorylation and Activation of Tau Kinases in Synucleinopathies and Alzheimer's Diseases. / Duka, Valeriy; Lee, Jae Hoon; Credle, Joel; Wills, Jonathan; Oaks, Adam; Smolinsky, Ciaran; Shah, Ketul; Mash, Deborah C; Masliah, Eliezer; Sidhu, Anita.

In: PLoS One, Vol. 8, No. 9, e75025, 20.09.2013.

Research output: Contribution to journalArticle

Duka, V, Lee, JH, Credle, J, Wills, J, Oaks, A, Smolinsky, C, Shah, K, Mash, DC, Masliah, E & Sidhu, A 2013, 'Identification of the Sites of Tau Hyperphosphorylation and Activation of Tau Kinases in Synucleinopathies and Alzheimer's Diseases', PLoS One, vol. 8, no. 9, e75025. https://doi.org/10.1371/journal.pone.0075025
Duka, Valeriy ; Lee, Jae Hoon ; Credle, Joel ; Wills, Jonathan ; Oaks, Adam ; Smolinsky, Ciaran ; Shah, Ketul ; Mash, Deborah C ; Masliah, Eliezer ; Sidhu, Anita. / Identification of the Sites of Tau Hyperphosphorylation and Activation of Tau Kinases in Synucleinopathies and Alzheimer's Diseases. In: PLoS One. 2013 ; Vol. 8, No. 9.
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AU - Lee, Jae Hoon

AU - Credle, Joel

AU - Wills, Jonathan

AU - Oaks, Adam

AU - Smolinsky, Ciaran

AU - Shah, Ketul

AU - Mash, Deborah C

AU - Masliah, Eliezer

AU - Sidhu, Anita

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N2 - Objective:Most neurodegenerative diseases contain hyperphosphorylated Tau [p-Tau]. We examined for the first time epitopes at which Tau is hyperphosphorylated in Parkinson's disease, dementia with Lewy bodies and Alzheimer's disease, and also select Tau kinases.Methods:Postmortem frontal cortex from Parkinson's disease, dementia with Lewy bodies, Alzheimer's disease and striata from Parkinson's disease, were analyzed by immunoblots using commercially available antibodies against 20 different phospho-epitopes of Tau. Major Tau kinases were also screened. Results in diseased tissues were compared to nondiseased controls.Results:In Alzheimer's disease, Tau was hyperphosphorylated at all the 20 epitopes of p-Tau. In dementia with Lewy bodies, p-Tau formation occurred at 6 sites sharing 30% overlap with Alzheimer's disease, while in Parkinson's frontal cortex, an area which does not degenerate, Tau hyperphosphorylation was seen at just 3 epitopes, indicating 15% overlap with Alzheimer's disease. In Parkinson's disease striatum, an area which undergoes considerable neurodegeneration, Tau was hyperphosphorylated at 10 epitopes, sharing 50% overlap with Alzheimer's disease. Between frontal cortex of Parkinson's disease and dementia with Lewy bodies, there were only two p-Tau epitopes in common. In striata of Parkinson's disease, there were 3 clusters of Tau hyperphosphorylated at 3 contiguous sites, while two such clusters were detected in dementia with Lewy bodies; such clusters disrupt axonal transport of mitochondria, cause microtubule remodeling and result in cell death. p-GSK-3β, a major Tau kinase, was activated in all brain regions examined, except in dementia with Lewy bodies. Activation of other Tau kinases was seen in all brain regions, with no clear pattern of activation.Interpretation:Our studies suggest that the three neurodegenerative diseases each have a signature-specific profile of p-Tau formation which may be useful in understanding the genesis of the diseases and for the development of a panel of specific biomarkers.

AB - Objective:Most neurodegenerative diseases contain hyperphosphorylated Tau [p-Tau]. We examined for the first time epitopes at which Tau is hyperphosphorylated in Parkinson's disease, dementia with Lewy bodies and Alzheimer's disease, and also select Tau kinases.Methods:Postmortem frontal cortex from Parkinson's disease, dementia with Lewy bodies, Alzheimer's disease and striata from Parkinson's disease, were analyzed by immunoblots using commercially available antibodies against 20 different phospho-epitopes of Tau. Major Tau kinases were also screened. Results in diseased tissues were compared to nondiseased controls.Results:In Alzheimer's disease, Tau was hyperphosphorylated at all the 20 epitopes of p-Tau. In dementia with Lewy bodies, p-Tau formation occurred at 6 sites sharing 30% overlap with Alzheimer's disease, while in Parkinson's frontal cortex, an area which does not degenerate, Tau hyperphosphorylation was seen at just 3 epitopes, indicating 15% overlap with Alzheimer's disease. In Parkinson's disease striatum, an area which undergoes considerable neurodegeneration, Tau was hyperphosphorylated at 10 epitopes, sharing 50% overlap with Alzheimer's disease. Between frontal cortex of Parkinson's disease and dementia with Lewy bodies, there were only two p-Tau epitopes in common. In striata of Parkinson's disease, there were 3 clusters of Tau hyperphosphorylated at 3 contiguous sites, while two such clusters were detected in dementia with Lewy bodies; such clusters disrupt axonal transport of mitochondria, cause microtubule remodeling and result in cell death. p-GSK-3β, a major Tau kinase, was activated in all brain regions examined, except in dementia with Lewy bodies. Activation of other Tau kinases was seen in all brain regions, with no clear pattern of activation.Interpretation:Our studies suggest that the three neurodegenerative diseases each have a signature-specific profile of p-Tau formation which may be useful in understanding the genesis of the diseases and for the development of a panel of specific biomarkers.

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