Familial multiple system tauopathy with presenile dementia: A disease with abundant neuronal and glial tau filaments

Spillantini, Maria Grazia; Goedert, Michel; Crowther, R. Anthony; Murrell, Jill R.; Farlow, Martin R.; Ghetti, Bernardino

doi:10.1073/pnas.94.8.4113

Cited by 324 publications

(232 citation statements)

References 45 publications

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“…Axonal swelling, vacuolization, and axonal spheroids are also seen in Drosophila (25) and some mouse tau Tg models (10,26,27). Also, dilated axons were reported in an FTDP-17 multiple system atrophy family (3,28). Both soluble and insoluble tau is phosphorylated at some of the same sites hyperphosphorylated in AD, FTDP-17, and other tauopathies (Fig.…”

Section: Discussionmentioning

confidence: 81%

Neurodegeneration and defective neurotransmission in a Caenorhabditis elegans model of tauopathy

Kraemer

Zhang

Leverenz

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

336

284

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Frontotemporal dementia with parkinsonism chromosome 17 type (FTDP-17) is caused by mutations in MAPT, the gene encoding tau. FTDP-17 begins with executive function deficits and other abnormal behaviors, which progress to dementia. Neurodegenerative changes include accumulation of aggregated tau as neuronal and glial fibrillary tangles. Aggregated tau is seen in numerous other neurodegenerative diseases, including Alzheimer's disease (AD). We expressed normal and FTDP-17 mutant human tau (mutations P 301 L and V 337 M ) in Caenorhabditis elegans to model tauopathy disorders. Tau pan-neuronal expression caused progressive uncoordinated locomotion (Unc), characteristic of nervous system defects in worms. Subsequently, insoluble tau accumulates and both soluble and insoluble tau is phosphorylated at many of the sites hyperphosphorylated in FTDP-17, AD, and other tauopathies. Substantial neurodegeneration, seen as bulges and gaps in nerve cords followed by loss of neurons, occurs after insoluble tau begins to accumulate. Axons show vacuoles, membranous infoldings, and whorls with associated amorphous tau accumulations and abnormal tau-positive aggregates. FTDP-17 mutation lines had a more severe Unc phenotype, accumulated more insoluble tau at a younger age, were more resistant to cholinergic inhibitors, and had more severe axonal degeneration when compared with lines expressing normal tau. The Unc phenotype is caused by a presynaptic defect. Postsynaptic transmission is intact. This transgenic model will enable mechanistic dissection of tau-induced neurodegeneration and identification of genes and compounds that inhibit pathological tau formation.A bnormally aggregated tau accumulates as neurofibrillary tangles and other lesions in many neurodegenerative diseases including Alzheimer's disease (AD) and frontotemporal dementia with parkinsonism chromosome 17 type (FTDP-17). For AD and most tauopathies, the role tau plays in disease initiation and progression is unknown. However, in FTDP-17, mutations in MAPT, the gene encoding tau, cause the disease (1-3), albeit by incompletely understood mechanisms. One hypothesis is that microtubule (MT)-mediated axonal transport is disrupted, an idea based on the reduced binding affinity of mutant tau for MTs (4). Another hypothesis is that aggregated tau is deleterious to cells, and in FTDP-17, aggregation is driven by either increased free tau concentrations (4) or mutationinduced acceleration of self-aggregation (5, 6). The critical toxic aggregate may be a dimer, a more extensive aggregate, tau filaments, or the end-stage tangles. The phosphorylation state of tau may also be important, as pathologic insoluble tau is hyperphosphorylated (7).To identify critical steps in tau-induced neurodegeneration, we generated a MAPT transgenic (Tg) Caenorhabditis elegans model of FTDP-17. Pan-neuronal expression of normal or FTDP-17 mutant MAPT resulted in altered behavior (uncoordinated movement), accumulation of insoluble phosphorylated tau, age-dependent loss of axons and neurons, and s...

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Section: Discussionmentioning

confidence: 81%

Neurodegeneration and defective neurotransmission in a Caenorhabditis elegans model of tauopathy

Kraemer

Zhang

Leverenz

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

336

284

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“…Mutation G389R also affects all six tau isoforms and the majority of filaments resemble the straight filaments of Alzheimer disease , despite the presence of Pick-like bodies by light microscopy. In contrast, in the case of mutations that increase the splicing of exon 10, the filaments appear as irregularly twisted ribbons, which are made of tau isoforms with four repeats (Spillantini et al 1997). In the case of mutation P301L in exon 10, which affects only four-repeat tau isoforms, the majority of filaments consists of narrow, irregularly twisted ribbons, with a smaller number of straight filaments (Spillantini et al 1998c).…”

Section: Implications For Understanding Alzheimer Diseasementioning

confidence: 99%

Frontotemporal Dementia: Implications for Understanding Alzheimer Disease

Goedert¹,

Ghetti²,

Spillantini³

2011

Cold Spring Harbor Perspectives in Medicine

138

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“…A subsequent immunohistochemical study demonstrated extensive similarities between the profile of immunodetectable polypeptides in LBs and Lewy neurites suggesting that both lesions result from a common pathogenic mechanism (Dickson et al, 1994). Spillantini et al, 1997a). Some well characterized`tauopathies' are: progressive supranuclear palsy, Pick's disease, corticobasal degeneration, familial frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) and Guam amyotrophic lateral sclerosis/parkinsonism dementia complex.…”

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confidence: 99%

Fatal attractions: abnormal protein aggregation and neuron death in Parkinson's disease and Lewy body dementia

et al. 1998

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The abnormal aggregation of proteins into fibrillar lesions is a neuropathological hallmark of several sporadic and hereditary neurodegenerative diseases. For example, Lewy bodies (LBs) are intracytoplasmic filamentous inclusions that accumulate primarily in subcortical neurons of patients with Parkinson's disease (PD), or predominantly in neocortical neurons in a subtype of Alzheimer's disease (AD) known as the LB variant of AD (LBVAD) and in dementia with LBs (DLB). Aggregated neurofilament subunits and a-synuclein are major protein components of LBs, and these inclusions may contribute mechanistically to the degeneration of neurons in PD, DLB and LBVAD. Here we review recent studies of the protein building blocks of LBs, as well as the role LBs play in the onset and progression of PD, DLB and LBVAD. Increased understanding of the protein composition and pathological significance of LBs may provide insight into mechanisms of neuron dysfunction and death in other neurodegenerative disorders characterized by brain lesions containing massive deposits of proteinacious fibrils.

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Familial multiple system tauopathy with presenile dementia: A disease with abundant neuronal and glial tau filaments

Cited by 324 publications

References 45 publications

Neurodegeneration and defective neurotransmission in a Caenorhabditis elegans model of tauopathy

Neurodegeneration and defective neurotransmission in a Caenorhabditis elegans model of tauopathy

Frontotemporal Dementia: Implications for Understanding Alzheimer Disease

Fatal attractions: abnormal protein aggregation and neuron death in Parkinson's disease and Lewy body dementia

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