M Goedert

..Moreover, the H1 haplotype of Tau has been identified as a significant risk factor for progressive supranuclear palsy and corticobasal degeneration...

..By the early 1990s, it was clear that tau protein is the major component of the paired helical filament and that the latter is made of all six tau isoforms, each full-length and hyperphosphorylated...

..More importantly, tau inclusions in the spinal cord of human P301S tau transgenic mice were labelled following a single intravenous injection of FSB. These findings indicate that FSB can be used to detect filamentous tau in vivo...

..In this article, we review the relevance of Lewy's discovery 100 years ago for the current understanding of PD and related disorders...

..Our findings provide direct evidence in favour of the degradation of tau aggregates by autophagy. Activation of autophagy may be worth investigating in the context of therapies for human tauopathies...

..They are not present in the pathological filamentous lesions and have not been found to be linked to genetic disease. The new work has established the alpha-synucleinopathies as a major class of neurodegenerative disease...

..Building on previous work, synthetic alpha-synuclein filaments have been shown to exhibit the characteristics of amyloid...

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..The new work has shown that dysfunction of tau protein causes neurodegeneration...

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..These findings indicate that missense mutations in tau lead to frontotemporal dementia through potentially multiple mechanisms...

..Several missense mutations also have a stimulatory effect on heparin-induced tau filament formation. Assembly of tau into filaments may be the gain of toxic function that is believed to underlie the demise of affected brain cells...

..The formation of intracellular filamentous inclusions might be the gain of toxic function that leads to the demise of affected brain cells...

..These findings indicate that alpha-synuclein forms the major filamentous component of Lewy bodies and Lewy neurites...

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..Although much has been written about Alzheimer, only little is known about Fischer. The present article discusses Fischer's work on dementia in the context of his life and time...

..This is consistent with the existence of multiple tau conformers and recent findings have provided experimental support for this concept...

..Genetic studies have shown that dysfunction of amyloid-beta or tau is sufficient to cause dementia. The ongoing molecular dissection of the neurodegenerative pathways is expected to lead to a true understanding of disease pathogenesis...

..His name will always be linked with the form of dementia that he described 100 years ago. Here we mark this anniversary by discussing Alzheimer's contributions to dementia research in the context of his life and times...

..At an experimental level, the new understanding is leading to the development of good transgenic animal models of the tauopathies...

..By exon trapping, the reduction in thermodynamic stability is correlated with increased splicing in of exon 10...

..Phosphorylation of a PDZ domain-containing protein by an associated protein kinase is a novel mechanism for determining both the localization and the substrate specificity of a protein kinase...

..Unlike SAPK2a and SAPK2b, SAPK4 and SAPK3 were not inhibited by the drugs SB 203580 and SB 202190. Our results suggest that cellular functions previously attributed to SAPK1 and/or SAPK2 may be mediated by SAPK3 or SAPK4...

..These findings double the number of candidate protein kinases for the hyperphosphorylation of tau in Alzheimer's disease and other neurodegenerative disorders...

..4 by PCR analysis of somatic cell hybrid DNA and by DNA hybridization to arrayed cosmids of the chromosome 19 metric physical map. This provides the first report of linked synaptotagmin genes...

..This result contrasts with previous studies of Ser-202 and Ser-396 which are partially phosphorylated in fetal tau, unphosphorylated in adult tau but almost fully phosphorylated in PHF tau...

..Taken together, the present findings indicate that the K257T mutation in Tau can cause a dementing condition similar to Pick's disease...

..Although the expression of most synaptotagmins predominates in neural tissue, we find that by contrast, synaptotagmin 6 is more abundant in thymus...

..These findings indicate that MAPs of the tau/MAP2/MAP4 family are found throughout much of the animal kingdom, where they may play a role in specialised processes requiring microtubules...

..The results show that dysregulation of tau protein production can cause neurodegeneration and imply that the FTDP-17 gene is the tau gene. This work has major implications for Alzheimer's disease and other tauopathies...

..We refer to the 140 and 134 amino acid proteins as alpha-synuclein and beta-synuclein, respectively. Both synucleins are expressed predominantly in brain, where they are concentrated in presynaptic nerve terminals...

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..Antisera raised against synthetic peptides corresponding to these different human tau isoforms demonstrate that multiple tau protein isoforms are incorporated into the neurofibrillary tangles of Alzheimer's disease...

..Taken in conjunction with previous findings, the present results indicate that both the three and four repeat-containing tau protein isoforms are present in the core of the paired helical filament...

..These antibodies, in conjunction with anti-tau antibodies, were used to demonstrate a close spatial relationship between amyloid deposits and neurofibrillary tangles...

..Transcripts encoding stress-activated protein kinase-3 are widely expressed, with high levels in skeletal muscle...

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..We show that protein phosphatase 2A is by far the major protein phosphatase activity in brain that dephosphorylates tau phosphorylated in this manner...

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..By exon trapping, the mutation produced an increase in the splicing in of exon 10, indicating that it probably causes disease through an overproduction of four-repeat tau...

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..The new work has established the alpha-synucleinopathies as a major class of neurodegenerative disease...

..It is expressed at high levels in rat brain, but not in spinal cord or a number of peripheral non-neuronal tissues...

..Messenger RNAs for MAP2 of high molecular mass are expressed both in cell bodies and in dendrites, consistent with the dendritic localization of the corresponding protein isoforms...

..Of the major serine/threonine protein phosphatases found in mammalian tissues only protein phosphatase 2A (PP2A) could dephosphorylate tau phosphorylated in this manner, with PP2A1 being the most effective form of the enzyme...

..The present results firmly establish that nerve cells constitute the major source in NGF in the brain. They also open the way to understanding the regulation of NGF biosynthesis in the central nervous system...

..The mas oncogene product was transiently expressed in Xenopus oocytes, and stably expressed in a transfected mammalian cell line. The results demonstrate that the mas gene product is a functional angiotensin receptor...

..These findings, which suggest a direct involvement of tau in axonal transport, have implications for understanding the pathogenesis of tauopathies...

..Filament assembly of synucleins was directly proportional to their degree of hydrophobicity and their tendency to form beta-sheet structure, and correlated inversely with their net charge...

..Thus, reactivation of the cell cycle was not involved in tau hyperphos-phorylation and filament formation, consistent with expression of p21Cip1 and p27Kip1 in tangle-bearing nerve cells...

..This type of tauopathy with GGIs expands the group of neurodegenerativedisorders in which oligodendroglial pathology predominates, beyond the synucleinopathy multiple system atrophy disorders...

..Phosphorylation by PKA and SAPK4/p38delta abolished the ability of tau to promote microtubule assembly, but failed to influence significantly the heparin-induced assembly of tau into filaments...

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..The late appearance and low abundance of tau ending at D421 indicate that it is unlikely that truncation at this site is necessary for the assembly of tau into filaments...

..Experimentally, the G335S mutation resulted in a greatly reduced ability of tau to promote microtubule assembly, while having no significant effect on heparin-induced assembly of recombinant tau into filaments...

..As before, the output of the algorithm, in the form of a simple x-y plot, was found to correlate very well with the location of alpha-helical structure in membrane bilayer-associated alpha-syn...

..This multidisciplinary study provides a comprehensive description of the natural history of disease in one of the largest known families with FTDP-17T...

..MSK1 phosphorylated S214, as well as S262, a KXGS site in the first repeat, and S305 in the second repeat...

..Taken together, these findings suggest that CK2 may be involved in the hyperphosphorylation of alpha-synuclein in alpha-synucleinopathies...

..Proc. Natl. Acad. Sci. USA 95, 7737-7741] reported a mutation at position + 3 in the intron following alternatively spliced exon 10 of the tau gene in a family...

..All six tau isoforms were present in soluble brain tau. Recombinant tau proteins with the L315R mutation showed a reduced ability to promote microtubule assembly...

..Recombinant tau protein with the S320F mutation showed a greatly reduced ability to promote microtubule assembly...

..By exon trapping, they increased the splicing of exon 10. DeltaN296 and N296H thus define a class of tau mutations with effects at both the RNA and the protein level...

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..These findings indicate that the aberrant activation of SAP kinases, especially SAPK3/p38gamma and SAPK4/p38delta, could play an important role in the abnormal hyperphosphorylation of tau that is an invariant feature of the tauopathies...

..Using both these approaches, we show here that native filaments from brain and filaments assembled in vitro from expressed tau protein have a clear cross-beta structure...

..We propose that loops in bound tau stabilize microtubules in a similar way to taxol, although with lower affinity so that assembly is reversible...

..The 34 amino acid insert positively influences both the rate and the extent of microtubule assembly, whereas the 53 amino acid insert only influences the extent of assembly...

..No evidence for apoptosis was obtained, despite the extensive colocalization of hyperphosphorylated tau protein with activated MAP kinase family members. The latter may be involved in the hyperphosphorylation of tau...

..These findings extend the number of candidate protein kinases for the hyperphosphorylation of tau in Alzheimer's disease and other neurodegenerative disorders...

..The lack of fibrils formed by beta-synuclein is most readily explained by the absence of a stretch of hydrophobic residues from the middle region of the protein. A model for the inhibition is proposed...

..These findings suggest a role for Tau in the adaptative response of neurons to stress and indicate that SAPK4/p38delta and/or SAPK3/p38delta may contribute to the hyperphosphorylation of Tau in the human tauopathies...

..Those findings establish Xenopus oocyte maturation as a system allowing the study of the functional effects of tau gene mutations in a quantitative manner...

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..Identification of small molecule inhibitors of heparin-induced assembly of tau will form a starting point for the development of mechanism-based therapies for the tauopathies...

..These findings suggest that inflammation may play a significant role in the events leading to neurodegeneration in the tauopathies and that anti-inflammatory compounds may have therapeutic potential...

..The observed effects on lipid binding and filament assembly may explain the pathogenic nature of the E46K mutation in alpha-synuclein...

..Sequencing of Saitohin revealed an intact open reading frame in chimpanzee and gorilla, but not in gibbon or macaque...

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..Our results are consistent with an in vivo role for the proteasome in tau degradation and support the existence of ubiquitin-independent pathways for the proteasomal degradation of unfolded proteins...

..Lewy bodies pathology is therefore unlikely to contribute significantly to the retention of PIB in positron emission tomography imaging studies...

..This is likely to regulate the integrity of intercellular-junctional complexes, and cell shape and volume in response to osmotic stress...

..This study provides further evidence of the clinical and pathological heterogeneity of DLB...

..These results identify a potential biological function for alpha-synuclein and define an omega-3-linked pathway leading to alpha-synuclein aggregation...

..These findings suggest that the C-terminal of alpha-synuclein is an important regulator of aggregation in vivo and will help to understand the mechanisms underlying the pathogenesis of Lewy body disorders and multiple system atrophy...

..To avoid potential artefacts, we recommend use of the Y136-TAT construct for the expression of human alpha-syn...

..The combination of these simple physicochemical properties with a previously described calculation of beta-strand contiguity allowed us to design mutations that changed the fibrillogenic propensity of alpha-synuclein in predictable ways...