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article

Tau protein phosphorylation at Thr¹⁷⁵ initiates fibril formation via accessibility of the N‐terminal phosphatase‐activating domain

Matthew A. Hintermayer, Kathryn Volkening, Alexander J. Moszczynski, Neil Donison, more

Journal of Neurochemistry > 155 > 3 > 313 - 326

One of the neuropathological hallmarks of the tauopathies is the formation of neuronal cytoplasmic inclusions and fibrils of microtubule‐associated tau protein (tau). The phosphorylation of Thr¹⁷⁵ of tau (pThr¹⁷⁵ tau) appears to be sufficient for fibril formation in vitro and in vivo, but the mechanism by which this initiates fibril formation is unknown. Using transient transfections of tau mutants...

article

Synergistic toxicity in an in vivo model of neurodegeneration through the co-expression of human TDP-43^M337V and tau^T175D protein

Alexander J. Moszczynski, Madeline Harvey, Niveen Fulcher, Cleusa Oliveira, more

Acta Neuropathologica Communications > 2019 > 7 > 1 > 1-17

Although it has been suggested that the co-expression of multiple pathological proteins associated with neurodegeneration may act synergistically to induce more widespread neuropathology, experimental evidence of this is sparse. We have previously shown that the expression of Thr¹⁷⁵Asp-tau (tau^T175D) using somatic gene transfer with a stereotaxically-injected recombinant adeno-associated virus (rAAV9)...

article

Untangling the Tauopathy for Alzheimer’s disease and parkinsonism

Hui-Yun Chang, Tzu-Kang Sang, Ann-Shyn Chiang

Journal of Biomedical Science > 2018 > 25 > 1 > 1-11

Tau is a microtubule-associated protein that mainly localizes to the axon to stabilize axonal microtubule structure and neuronal connectivity. Tau pathology is one of the most common proteinopathies that associates with age-dependent neurodegenerative diseases including Alzheimer’s disease (AD), and various Parkinsonism. Tau protein undergoes a plethora of intra-molecular modifications and some altered...

article

Threonine¹⁷⁵, a novel pathological phosphorylation site on tau protein linked to multiple tauopathies

Alexander J. Moszczynski, Wencheng Yang, Robert Hammond, Lee Cyn Ang, more

Acta Neuropathologica Communications > 2017 > 5 > 1 > 1-14

Microtubule associated protein tau (tau) deposition is associated with a spectrum of neurodegenerative diseases collectively termed tauopathies. We have previously shown that amyotrophic lateral sclerosis (ALS) with cognitive impairment (ALSci) is associated with tau phosphorylation at Thr¹⁷⁵ and that this leads to activation of GSK3β which then induces phosphorylation at tau Thr²³¹. This latter step...

article

ALS/FTLD: experimental models and reality

Rachel H. Tan, Yazi D. Ke, Lars M. Ittner, Glenda M. Halliday

Acta Neuropathologica > 2017 > 133 > 2 > 177-196

Amyotrophic lateral sclerosis is characterised by a loss of upper and lower motor neurons and characteristic muscle weakness and wasting, the most common form being sporadic disease with neuronal inclusions containing the tar DNA-binding protein 43 (TDP-43). Frontotemporal lobar degeneration is characterised by atrophy of the frontal and/or temporal lobes, the most common clinical form being the behavioural...

article

The microtubule associated protein tau H1 haplotype and risk of essential tremor

L. N. Clark, X. Liu, N. L. Parmalee, N. Hernandez, more

European Journal of Neurology > 21 > 7 > 1044 - 1048

Background and purposeTwo recent studies investigated the association of the microtubule associated protein tau (MAPT) H1 haplotype, a known risk factor for neurodegenerative disease including progressive supranuclear palsy and Parkinson's disease (PD), with essential tremor (ET). MethodsTo confirm this association in a different population the distribution of allele and genotype frequencies for...

article

Frontal asymmetry in behavioral variant frontotemporal dementia: clinicoimaging and pathogenetic correlates

Jennifer L. Whitwell, Jia Xu, Jay Mandrekar, Bradley F. Boeve, more

Neurobiology of Aging > 2013 > 34 > 2 > 636-639

We aimed to assess associations between clinical, imaging, pathologic, and genetic features and frontal lobe asymmetry in behavioral variant frontotemporal dementia (bvFTD). Volumes of the left and right dorsolateral, medial, and orbital frontal lobes were measured in 80 bvFTD subjects and subjects were classified into 3 groups according to the degree of asymmetry (asymmetric left, asymmetric right,...

article

Do interactions between SNCA, MAPT, and LRRK2 genes contribute to Parkinson’s disease susceptibility?

Joanna M. Biernacka, Sebastian M. Armasu, Julie M. Cunningham, J. Eric Ahlskog, more

Parkinsonism and Related Disorders > 2011 > 17 > 10 > 730-736

Polymorphisms in SNCA, MAPT and LRRK2 genes have recently been confirmed as risk factors for Parkinson’s disease (PD), although with small individual attributable risk. Here we investigated the association of PD with interactions between variants of these genes.As part of a previous study of PD susceptibility genes 119 SNCA, MAPT, and LRRK2 haplotype tagging single nucleotide polymorphisms (SNPs)...

article

Genome‐Wide Association Study Confirms SNPs in SNCA and the MAPT Region as Common Risk Factors for Parkinson Disease

Todd L. Edwards, William K. Scott, Cherylyn Almonte, Amber Burt, more

Annals of Human Genetics > 74 > 2 > 97 - 109

Parkinson disease (PD) is a chronic neurodegenerative disorder with a cumulative prevalence of greater than one per thousand. To date three independent genome‐wide association studies (GWAS) have investigated the genetic susceptibility to PD. These studies implicated several genes as PD risk loci with strong, but not genome‐wide significant, associations. In this study, we combined data from two previously...

article

Transgenic Drosophila models of Alzheimer’s disease and tauopathies

Kanae Iijima-Ando, Koichi Iijima

Brain Structure and Function > 2010 > 214 > 2-3 > 245-262

Alzheimer’s disease (AD) is the most common form of senile dementia. Aggregation of the amyloid-β42 peptide (Aβ42) and tau proteins are pathological hallmarks in AD brains. Accumulating evidence suggests that Aβ42 plays a central role in the pathogenesis of AD, and tau acts downstream of Aβ42 as a modulator of the disease progression. Tau pathology is also observed in frontotemporal dementia with...

article

α-Synuclein Promotes the Recruitment of Tau to Protein Inclusions in Oligodendroglial Cells: Effects of Oxidative and Proteolytic Stress

Michael Riedel, Olaf Goldbaum, Christiane Richter-Landsberg

Journal of Molecular Neuroscience > 2009 > 39 > 1-2 > 226-234

α-Synuclein is the major building block of cytoplasmic inclusions in neurodegenerative disorders named synucleinopathies. These inclusion bodies often contain the small heat shock protein αB-crystallin and the microtubule-associated protein tau. Oxidative modification of α-synuclein has been linked to fibril formation, and α-synuclein aggregation may induce the fibrillization of tau. To study α-synuclein...

article

High throughput screening for small molecule inhibitors of heparin-induced tau fibril formation

Alex Crowe, Carlo Ballatore, Edward Hyde, John Q. Trojanowski, more

Biochemical and Biophysical Research Communications > 2007 > 358 > 1 > 1-6

A library of ∼51,000 compounds was interrogated by high throughput screening (HTS) using a heparin-induced tau fibrillization assay. HTS was conducted with bacterially expressed recombinant tau fragment K18 and the reaction was monitored by thioflavine T fluorescence. Hits meeting criteria set for selection in HTS were further evaluated in a panel of assays designed (a) to confirm the initial results...

article

Significance and mechanism of alzheimer neurofibrillary degeneration and therapeutic targets to inhibit this lesion

Khalid Iqbal, Alejandra Del C. Alonso, Ezzat El-Akkad, Cheng-Xin Gong, more

Journal of Molecular Neuroscience > 2002 > 19 > 1-2 > 95-99

Abnormally hyperphosphorylated tau which is the major protein subunit of paired helical filaments (PHF)/neurofibrillary tangles is the pivotal lesion in Alzheimer disease (AD) and related tauopathies. The cosegregation of tau mutations with disease in inherited cases of frontotemporal dementia has confirmed that abnormalities in this protein can be a primary cause of neurodegeneration. Unlike normal...

article

Multiple Forms of Phosphatase from Human Brain: Isolation and Partial Characterization of Affi-Gel Blue Binding Phosphatases

Li Yao Cheng, Jian-Zhi Wang, Cheng-Xin Gong, Jin-Jing Pei, more

Neurochemical Research > 2000 > 25 > 1 > 107-120

Implication of protein phosphatases in Alzheimer disease led us to a systemic investigation of the identification of these enzyme activities in human brain. Human brain phosphatases eluted from DEAE-Sephacel with 0.22 M NaCl were resolved into two main groups by affi-gel blue chromatography, namely affi-gel blue-binding phosphatases and affi-gel blue-nonbinding phosphatases. Affi-gel blue-binding...

article

Bovine and human tau, highly homologous but less crossreactive: implications for Alzheimer disease

Alejandra del C. Alonso, Inge Grundke-Iqbal, Khalid Iqbal

Molecular Brain Research > 1995 > 31 > 1-2 > 194-200

Tau is a highly conserved protein during evolution. However, polymerization of tau into paired helical filaments, a characteristic of Alzheimer disease is unique to humans and has not been seen in animals. The cause of this phenomenon is not known. The cDNA-derived amino acid sequences of bovine and human tau are highly homologous. In this study we show that despite the high homology there are...

article

Phosphorylation and accumulation of tau without any concomitant increase in tubulin levels in Chinese Hamster Ovary cells stably transfected with human tau ₄ ₄ ₁

Niloufar Haque, Robert B. Denman, George Merz, Inge Grundke-Iqbal, more

FEBS Letters > 1995 > 360 > 2 > 132-136

Eucaryotic expression vectors bearing a 1.4 kb cDNA encoding the 4 repeat isoform of human tau, tau ₄ ₄ ₁ , in either the sense or anti-sense orientation with respect to a cytomegalovirus (CMV) promoter were constructed. The resulting constructs were used to transiently express tau in Chinese Hamster Ovary cells and to generate non-neuronal stable cell lines. Immunocytochemical studies...

article

Levels of normal and abnormally phosphorylated tau in different cellular and regional compartments of Alzheimer disease and control brains

Sabiha Khatoon, Inge Grundke-Iqbal, Khalid Iqbal

FEBS Letters > 1994 > 351 > 1 > 80-84

Microtubule associated protein tau is abnormally phosphorylated in Alzheimer disease (AD) brain. In the present study we investigated (i) whether tau is axonal or both axonal and somatodendritic, (ii) whether tau is a marker of Alzheimer neurofibrillary pathology, and (iii) whether the levels of tau in the cytosol (100,000 x g supernate) from AD brain are altered. Frozen autopsied tissue from 20 AD,...

article

Alzheimer paired helical filaments Restoration of the biological activity by dephosphorylation

Khalid Iqbal, Tanweer Zaidi, Christian Bancher, Inge Grundke-Iqbal

FEBS Letters > 1994 > 349 > 1 > 104-108

In a normal mature neuron, microtubule associated protein tau promotes the assembly of tubulin into microtubules and maintains the structure of microtubules. In Alzheimer disease brain, tau is abnormally hyperphosphorylated and is the major protein subunit of paired helical filaments PHF). In the present study, the biological activity of tau in PHF and the effect of dephosphorylation on this activity...

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