Identification of amino‐terminally cleaved tau fragments that distinguish progressive supranuclear palsy from corticobasal degeneration

Arai, Tetsuaki; Ikeda, Kenji; Akiyama, Haruhiko; Nonaka, Takashi; Hasegawa, Masato; Ishiguro, Koichi; Iritani, Shuji; Tsuchiya, Kuniaki; Iseki, Eizo; Yagishita, Saburo; Oda, Tatsuro; Mochizuki, Akihide

doi:10.1002/ana.10793

Cited by 163 publications

(133 citation statements)

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“…In contrast, tau35 was recognised on western blots probed with antibodies p199/202, AT8, p212 and TP70, the epitopes of which lie between residue 199/202 and the extreme C-terminus of tau, respectively. These results suggest that cleavage of intact tau to generate tau35 occurs between residues 181 and 199/202, consistent with N-terminal truncation of tau in PSP as suggested previously by Arai et al (2004). Furthermore, the immunoreactivity of phospho-specific tau antibodies with tau35 indicates that it is phosphorylated similarly to intact PSP-tau, at least at the epitopes recognised by antibodies p199/p202, AT8, p212 and PHF1.…”

Section: Resultssupporting

confidence: 88%

“…Using mass spectrometry, we determined that tau35 has an intact C-terminus, but lacks the N-terminus, the most N-terminal residue detected being Ser195, and that it contained the fourth microtubule-binding repeat of tau encoded for by exon. Tau35 may correspond to the 33 kDa tau fragment reported previously in PSP brain (Arai et al 2004). We have shown that the cleavage point on tau that leads to the production of tau35 resides between residues 182 and 194 in a similar region to the 33 kDa fragment described by Arai et al that is apparently generated by cleavage of tau at residue 187.…”

Section: Discussionsupporting

confidence: 75%

“…S1). Taken together with existing phospho-specific antibody evidence for tau phosphorylation at Thr181, Ser199, Ser202, Ser205, Thr212, Ser214, Thr231, Ser262, Ser396, Ser404, Ser409, Ser413, Ser422, this brings to 16 the total number of phosphorylation sites presently identified on PSP-tau (Sergeant et al 1999;Arai et al 2004).…”

Section: Mass Spectrometric Analysis Of Psp-tausupporting

confidence: 53%

“…Cleavage of tau has also been suggested to be important in disease, and specific fragments of tau that lack the N-terminus may be useful in distinguishing PSP from corticobasal degeneration (CBD) (Arai et al 2001b;Arai et al 2004). The presence of a C-terminal tau fragment in CSF might also have potential use as a diagnostic tool, with a reduced amount of this fragment being detected in CSF from PSP patients than from other tauopathies (Borroni et al 2007).…”

mentioning

confidence: 99%

“…Several studies have enriched PHF-tau from Alzheimer brain and identified sites of phosphorylation by direct sequencing, with the current number of directly identified tau phosphorylation sites standing at 39 (Morishima-Kawashima et al 1995;Hanger et al 1998Hanger et al , 2007. Several phosphorylation sites have been identified on PSP-tau by the use of phosphospecific antibodies (Arai et al 2004;Puig et al 2005), but to date there has been no direct sequence analysis of PSP-tau to identify specific phosphorylated residues. This is likely due to the difficulty in extracting sufficient tau from PSP postmortem brain tissue using methods developed for the more abundant PHF-tau present in Alzheimer brain.…”

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confidence: 99%

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Direct analysis of tau from PSP brain identifies new phosphorylation sites and a major fragment of N‐terminally cleaved tau containing four microtubule‐binding repeats

Wray

Saxton

Anderton

et al. 2008

Journal of Neurochemistry

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Tangles containing hyperphosphorylated aggregates of insoluble tau are a pathological hallmark of progressive supranuclear palsy (PSP). Several phosphorylation sites on tau in PSP have been identified using phospho-specific antibodies, but no sites have been determined by direct sequencing due to the difficulty in enriching insoluble tau from PSP brain. We describe a new method to enrich insoluble PSP-tau and report eight phosphorylation sites [Ser46, Thr181, Ser202, Thr217, Thr231, Ser235, Ser396/Ser400 (one site) and Thr403/Ser404 (one site)] identified by mass spectrometry. We also describe a 35 kDa C-terminal tau fragment (tau35), lacking the N-terminus of tau but containing four microtubule-binding repeats (4R), that is present only in neurodegenerative disorders in which 4R tau is over-represented. Tau35 was readily detectable in PSP, corticobasal degeneration and 4R forms of fronto-temporal dementia with parkinsonism linked to chromosome 17, but was absent from control, Alzheimer's disease and Pick's disease brain. Our findings suggest the aggregatory characteristics of PSP-tau differ from those of insoluble tau in Alzheimer's disease brain and this might be related to the presence of a C-terminal cleavage product of tau.

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Section: Resultssupporting

confidence: 88%

Section: Discussionsupporting

confidence: 75%

Section: Mass Spectrometric Analysis Of Psp-tausupporting

confidence: 53%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Direct analysis of tau from PSP brain identifies new phosphorylation sites and a major fragment of N‐terminally cleaved tau containing four microtubule‐binding repeats

Wray

Saxton

Anderton

et al. 2008

Journal of Neurochemistry

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Progression in Frontotemporal Dementia

Davies¹,

Kipps²,

Mitchell³

et al. 2006

Arch Neurol

173

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To assess the clinical course and prognosis in patients with behavioral-variant frontotemporal dementia (FTD) lacking evidence of brain atrophy on magnetic resonance imaging (MRI).Design: Patients were enrolled into this prospective cohort study over a period of 15 years; cognitive status, duration of symptoms, and behavioral indexes were recorded. Brain MRIs were rated using a standardized scale. Setting: Regional early-onset dementia clinic.Participants: Thirty-one participants diagnosed clinically with behavioral-variant FTD.Intervention: Rating of MRIs.Main Outcome Measures: Death or institutionalization after a minimum of 3 years' follow-up indicated poor prognosis, while the ability to live independently was re-garded as a good prognosis for the purpose of survival (Kaplan-Meier) and discriminant function analysis.Results: Patients with normal or borderline MRI findings (n=15) showed significantly longer survival to institutionalization or death than those (n=16) with definite frontotemporal atrophy (mean±SE, 9.3±1.7 years vs 3.0±0.7 years; PϽ.01). Using groups defined by 3-year outcome (good or bad prognosis), cerebral atrophy predicted poor outcome while age, symptom duration, cognitive performance, behavioral impairment, and overall disability at baseline did not.Conclusions: Patients with FTD with normal MRI results follow a more benign course than cases with atrophy at presentation. The substrate of the behavioral symptoms in such cases may differ from the neurodegenerative pathological features typically associated with FTD.

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Progressive Supranuclear Palsy

Josephs

2015

Encyclopedia of Life Sciences

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Progressive supranuclear palsy (PSP) is a neurodegenerative disease that was first described approximately 50 years ago in 1964. When first described, PSP was thought to have a unique clinical presentation characterised by loss of balance leading to early falls, slowness of movements, stiffness of muscles and loss of the ability to voluntarily move the eyes up and down. Subsequently, it has been recognised that patients who have died and have shown microscopic changes in the brain consistent with PSP had other clinical presentations not involving balance, falls or eye movement problems. The term PSP is, therefore, now best reserved for pathological diagnosis. There have been numerous advances in our understanding of PSP, including the fact that patients with PSP can have many different clinical presentations. In this review, we will focus on the pathological, clinical, neuroimaging and genetic characteristics of PSP. Key Concepts Progressive supranuclear palsy (PSP) is a pathological diagnosis. The cause of PSP is unknown but is thought to be related to abnormal hyperphosphorylated 4R tau. PSP can present as one of many different clinical syndromes. Impaired balance with early falls and vertical eye movement problems are highly predictive of PSP pathology. Atrophy of the premotor cortex, midbrain and superior cerebellar peduncle are the main MRI findings in PSP. There is some evidence that PSP could have genetic underpinnings.

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Identification of amino‐terminally cleaved tau fragments that distinguish progressive supranuclear palsy from corticobasal degeneration

Cited by 163 publications

References 37 publications

Direct analysis of tau from PSP brain identifies new phosphorylation sites and a major fragment of N‐terminally cleaved tau containing four microtubule‐binding repeats

Direct analysis of tau from PSP brain identifies new phosphorylation sites and a major fragment of N‐terminally cleaved tau containing four microtubule‐binding repeats

Progression in Frontotemporal Dementia

Progressive Supranuclear Palsy

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