Home > A. Molecular pathology > tauopathies
tauopathies
Friday 17 October 2003
Definition: The tauopathies (or ’taupathies are a group of neurodegenerative disorders characterized by the presence of filamentous deposits, consisting of hyperphosphorylated tau protein, in neurons and glia. Abnormal tau phosphorylation and deposition in neurones and glial cells is one of the major features in taupathies.
Images
globose tangles in progressive supranuclear palsy (PSP) case (substantia nigra ). Immuno is tau .
The term " tauopathy ", which was first used to describe a family with frontotemporal dementia (FTD) and abundant tau deposits (Spillantini et al., 1997), is now used to identify a group of diseases with widespread tau pathology in which tau accumulation appears to be directly associated with neuronal death and disease development.
Major neurodegenerative tauopathies includes sporadic and hereditary neurodegenerative diseases characterized by filamentous tau deposits in brain and spinal cord.
In prototypical tauopathies, glial and neuronal tau inclusions are the sole or predominant CNS lesions. They includes
amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS-FTDP )
argyrophilic grain dementia
diffuse neurofibrillary tangles with calcification
frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17 )
corticobasal degeneration (CBD)
Pick disease
progressive supranuclear palsy (PSP)
progressive subcortical gliosis (PSG)
tangle only dementia
By extension, tauopathies caracterize a larger group of diseases in which significant filaments and aggregates of tau protein are found. They includes :
sporadic/familial Alzheimer disease (AD)
amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS-FTDP)
argyrophilic grain dementia
dementia pugilistica
diffuse neurofibrillary tangles with calcification
Down syndrome
frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17)
Gerstmann-Straussler-Scheinker disease
Hallervorden-Spatz disease
inclusion body myositis
Creutzfeld-Jakob disease (CJD)
multiple system atrophy
Niemann-Pick disease type C (NPC)
Pick disease
prion protein cerebral amyloid angiopathy
progressive supranuclear palsy (PSP)
subacute sclerosing panencephalitis
tangle-predominant Alzheimer disease
frontotemporal dementia (FTD)
corticobasal degeneration (CBD)
myotonic dystrophy
non-guanamian motor neuron disease with neurofibrillary tangles
postencephalitic parkinsonism
prion protein cerebral amyloid angiopathy
progressive subcortical gliosis
subacute sclerosing panencephalitis
tangle only dementia
Mutations of MAPT gene coding for tau protein are found only in:
17q21-linked presenile dementia (MIM.600274)
17q21-linked familial frontotemporal dementia (MIM.600274)
17q21-linked frontotemporal dementia with parkinsonism (FTDP-17) (MIM.600274)
17q21-linked parkinsonism
17q21-linked Pick disease (MIM.172700)
17q21-linked progressive supranuclear palsy (PSP) (MIM.601104) (rare)
17q21-linked atypical progressive supranuclear palsy (atypical PSP) (MIM.260540) (rare)
fatal respiratory hypoventilation (14595660)
Four types of MAPT mutations
missense mutations
silent mutations
deletion mutation
intronic mutations (afetr exon 10)
Loclaization of Tau filaments
neurones and glial cells
- frontotemporal dementia with parkinsonism (FTDP-17)
- progressive supranuclear palsy (PSP)
- corticobasal degeneration (CBD)
- PSG
- Prion disease (PiD) and Creutzfeld-Jakob disease (CJD)
The term tauopathies also can be extended to other neurodegenerative
diseases where tau pathology is found in conjunction with other abnormal protein lesions, such as Alzheimer disease (AD), or occasionally with other diseases where prion protein, Bri, or α-synuclein (SNCA) are aggregated. Such disorders may be considered secondary
tauopathies, and in these diseases, although tau is probably not the initial pathological factor, tau aggregates contribute to the final degeneration.
Tau deposits can also be found in several other neurodegenerative diseases in which tau pathology is evident in conjunction with other abnormal protein lesions, such as Alzheimer disease (AD). Abundant cytoplasmic inclusions consisting of aggregated hyperphosphorylated protein tau are a characteristic pathological observation in several neurodegenerative disorders such as Alzheimer’s disease, Pick’s disease, frontotemporal dementia, cortico-basal degeneration and progressive supranuclear palsy.
Classification
Tau deposits can also be found in many neurodegenerative diseases in which tau pathology is evident in conjunction with other abnormal protein lesions, such as Alzheimer disease (AD).
Abundant cytoplasmic inclusions consisting of aggregated hyperphosphorylated protein tau are a characteristic pathological observation in several neurodegenerative disorders such as Alzheimer’s disease, Pick’s disease, frontotemporal dementia, cortico-basal degeneration and progressive supranuclear palsy.
tau protein aggregation and accumulation
- Alzheimer disease
- Pick disease
- frontotemporal dementia (FTD)
- cortico-basal degeneration (CBD)
- progressive supranuclear palsy (PSP)
tau protein mutations
ch. 17 linked presenile dementia
ch. 17 linked familial frontotemporal dementia
ch. 17 linked parkinsonism
Model of tauopathies
Tau is central in the AD-FTD spectrum. A speculative model for tau-mediated neurodegeneration in the genetic AD-FTD spectrum of brain disorders. In addition to tau pathology, APP and typical PSENs mutations lead to Aβ-positive pathology causing vascular damage and hence neuronal death.
By contrast, genetic alterations in MAPT lead to Aβ-independent tau-mediated neuronal death.
Loss of PSENs function might result in Aβ-negative tau-mediated neurodegeneration further emphasizing that tau is the central molecule in the AD-FTD spectrum.
Neurofibrillary tangles (NFTs) and Tau aggregation
In NFTs, Tau proteins are hyperphosphorylated (PHF-tau). They can be full-length or cleaved by CASP6.
Tau aggregation
phosphorylation
ubiquitination
oxidation
glycation
co-factors
Therapeutics
NFTs formation blocking
- blocking peptides
- immunotherapy vs phosphorylated tau
kinase inhibitors
- lithium blocking GSK3beta
microtubule stabilization
- taxol
References
Dermaut B, Kumar-Singh S, Rademakers R, Theuns J, Cruts M, Van Broeckhoven C. Tau is central in the genetic Alzheimer-frontotemporal dementia spectrum. Trends Genet. 2005 Dec;21(12):664-72. PMID: 16221505
Laferla FM, Oddo S. Alzheimer’s disease: Abeta, tau and synaptic dysfunction. Trends Mol Med. 2005 Apr;11(4):170-6. PMID: 15823755
D’Souza I, Schellenberg GD. Regulation of tau isoform expression and dementia. Biochim Biophys Acta. 2005 Jan 3;1739(2-3):104-15. PMID: 15615630
Goedert M, Jakes R. Mutations causing neurodegenerative tauopathies. Biochim Biophys Acta. 2005 Jan 3;1739(2-3):240-50. PMID: 15615642
Iqbal K, Alonso Adel C, Chen S, Chohan MO, El-Akkad E, Gong CX, Khatoon S, Li B, Liu F, Rahman A, Tanimukai H, Grundke-Iqbal I. Tau pathology in Alzheimer disease and other tauopathies. Biochim Biophys Acta. 2005 Jan 3;1739(2-3):198-210. PMID: 15615638
von Bergen M, Barghorn S, Biernat J, Mandelkow EM, Mandelkow E. Tau aggregation is driven by a transition from random coil to beta sheet structure. Biochim Biophys Acta. 2005 Jan 3;1739(2-3):158-66. Epub 2004 Nov 12. PMID: 15615635
Hyman BT, Augustinack JC, Ingelsson M. Transcriptional and conformational changes of the tau molecule in Alzheimer’s disease. Biochim Biophys Acta. 2005 Jan 3;1739(2-3):150-7. PMID: 15615634
Gamblin TC. Potential structure/function relationships of predicted secondary structural elements of tau. Biochim Biophys Acta. 2005 Jan 3;1739(2-3):140-9. PMID: 15615633
Yancopoulou D, Spillantini MG. Tau protein in familial and sporadic diseases. Neuromolecular Med. 2003;4(1-2):37-48. PMID: 14528051
Hutton M, Lewis J, Dickson D, Yen SH, McGowan E. Analysis of tauopathies with transgenic mice. Trends Mol Med. 2001 Oct;7(10):467-70. PMID: 11597522
Avila J. Tau aggregation into fibrillar polymers: taupathies. FEBS Lett. 2000 Jun 30;476(1-2):89-92. PMID: 10878257
Heutink P. Untangling tau-related dementia. Hum Mol Genet. 2000 Apr 12;9(6):979-86. PMID: 10767321
