Corticobasal degeneration and progressive supranuclear palsy share a common tau haplotype

Houlden, Henry; Baker, Mary V.; Morris, Huw R.; MacDonald, Neil; Pickering‐Brown, Stuart; Adamson, Jennifer; Lees, Andrew J.; Rossor, Martin N.; Quinn, Niall; Kertesz, Andrew; Khan, M. Nadeem; Hardy, John; Lantos, Peter L.; George‐Hyslop, Peter St; Muñoz, David G.; Mann, Dave; Lang, Anthony E.; Bergeron, Catherine; Bigio, Eileen H.; Litvan, Irene; Bhatia, Kailash P.; Dickson, Dennis W.; Wood, Nicholas W.; Hutton, Mike

doi:10.1212/wnl.56.12.1702

Cited by 382 publications

(206 citation statements)

References 29 publications

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“…208 -211 In addition, sporadic tauopathies are strongly correlated with the MAPT H1 haplotype, from which approximately 1.4-fold more four-repeat tau isoforms are generated than from the H2 haplotype. 63,64,212 No difference in the ratio of four-and three-repeat isoforms was found in total postmortem AD brain tau, but a roughly 1.5-fold excess of four-repeat tau has been reported in the temporal cortices of AD brains. 207,213,214 Four-repeat tau binds microtubules with a higher affinity than three-repeat tau, and an isoform imbalance in favor of four-repeat isoforms might impair kinesin-dependent anterograde traffic, because tau and kinesins bind to the microtubule surface in a competitive fashion.…”

Section: Isoform Approachesmentioning

confidence: 95%

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Tau-Based Treatment Strategies in Neurodegenerative Diseases

2008

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Summary:Neurofibrillary tangles are a characteristic hallmark of Alzheimer's and other neurodegenerative diseases, such as Pick's disease (PiD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). These diseases are summarized as tauopathies, because neurofibrillary tangles are composed of intracellular aggregates of the microtubule-associated protein tau. The molecular mechanisms of tau-mediated neurotoxicity are not well understood; however, pathologic hyperphosphorylation and aggregation of tau play a central role in neurodegeneration and neuronal dysfunction. The present review, therefore, focuses on therapeutic approaches that aim to inhibit tau phosphorylation and aggregation or to dissolve preexisting tau aggregates. Further experimental therapy strategies include the enhancement of tau clearance by activation of proteolytic, proteasomal, or autophagosomal degradation pathways or anti-tau directed immunotherapy. Hyperphosphorylated tau does not bind microtubules, leading to microtubule instability and transport impairment. Pharmacological stabilization of microtubule networks might counteract this effect. In several tauopathies there is a shift toward four-repeat tau isoforms, and interference with the splicing machinery to decrease four-repeat splicing might be another therapeutic option.

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Section: Isoform Approachesmentioning

confidence: 95%

“…61,62 Similar findings have been obtained in PSP and CBD, two tauopathies that share the MAPT H1 haplotype as a risk factor. 63,64 Filamentous tau aggregates in PSP and CBD consist of four-repeat isoforms. 65 Why tau, a highly soluble protein, aggregates into PHFs is still a matter of debate.…”

Section: Pathophysiologymentioning

confidence: 99%

Tau-Based Treatment Strategies in Neurodegenerative Diseases

2008

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“…The H2 haplotype is likely to be protective as it is associated with increased expression of exon 3 of MAPT in grey matter, which has an inhibitory role in tau aggregation, unlike exons 2 and 10 which promote aggregation [21]. The H1 haplotype and sub-haplotype H1c are risk factors for PSP and CBD [22].…”

Section: Geneticsmentioning

confidence: 99%

Untangling the tauopathies: Current concepts of tau pathology and neurodegeneration

Ling

2018

Parkinsonism & Related Disorders

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“…Wealso have had a case of clinically probable corticobasal degeneration (GBD) with the procerus sign. The relationship between PSP and CBDhas yet to be clarified (2,3), but this sign maybe important in the association of these diseases clinically. Therefore, we give a summaryof our case.…”

mentioning

confidence: 99%

“…Electromyography (EMG) should provide useful informationabout whatthis sign represents. PSP and CBDhave characteristics in commonneuropathologically and genetically, e.g., the tau haplotype (2). Both diseases are neuropathologically characterized by selective 4-repeat tau deposition.…”

mentioning

confidence: 99%