Article

Tumor suppressor PTEN affects tau phosphorylation: deficiency in the phosphatase activity of PTEN increases aggregation of an FTDP-17 mutant Tau

Center for Neuroscience and Aging, Burnham Institute for Medical Research, 10901 N, Torrey Pines Road, La Jolla, CA 92037, USA.
Molecular Neurodegeneration (Impact Factor: 5.29). 02/2006; 1:7. DOI: 10.1186/1750-1326-1-7
Source: PubMed

ABSTRACT Aberrant hyperphosphorylation of tau protein has been implicated in a variety of neurodegenerative disorders. Although a number of protein kinases have been shown to phosphorylate tau in vitro and in vivo, the molecular mechanisms by which tau phosphorylation is regulated pathophysiologically are largely unknown. Recently, a growing body of evidence suggests a link between tau phosphorylation and PI3K signaling. In this study, phosphorylation, aggregation and binding to the microtubule of a mutant frontal temporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) tau in the presence of tumor suppressor PTEN, a major regulatory component in PI3K signaling, were investigated.
Phosphorylation of the human mutant FTDP-17 tau, T40RW, was evaluated using different phospho-tau specific antibodies in the presence of human wild-type or phosphatase activity null mutant PTEN. Among the evaluated phosphorylation sites, the levels of Ser214 and Thr212 phospho-tau proteins were significantly decreased in the presence of wild-type PTEN, and significantly increased when the phosphatase activity null mutant PTEN was ectopically expressed. Fractionation of the mutant tau transfected cells revealed a significantly increased level of soluble tau in cytosol when wild-type PTEN was expressed, and an elevated level of SDS-soluble tau aggregates in the presence of the mutant PTEN. In addition, the filter/trap assays detected more SDS-insoluble mutant tau aggregates in the cells overexpressing the mutant PTEN compared to those in the cells overexpressing wild-type PTEN and control DNA. This notion was confirmed by the immunocytochemical experiment which demonstrated that the overexpression of the phosphatase activity null mutant PTEN caused the mutant tau to form aggregates in the COS-7 cells.
Tumor suppressor PTEN can alleviate the phosphorylation of the mutant FTDP-17 tau at specific sites, and the phosphatase activity null PTEN increases the mutant tau phosphorylation at these sites. The changes of the tau phosphorylation status by ectopic expression of PTEN correlate to the alteration of the mutant tau's cellular distribution. In addition, the overexpression of the mutant PTEN can increase the level of the mutant tau aggregates and lead to the formation of visible aggregates in the cells.

0 Followers
 · 
78 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Network-based systems biology tools including Pathway Studio 9.0 were used to identify Parkinson's disease (PD) critical molecular players, drug targets, and underlying biological processes. Utilizing several microarray gene expression datasets, biomolecular networks such as direct interaction, shortest path, and microRNA regulatory networks were constructed and analyzed for the disease conditions. Network topology analysis of node connectivity and centrality revealed in combination with the guilt-by-association rule 17 novel genes of PD-potential interest. Seven new microRNAs (miR-132, miR-133a1, miR-181-1, miR-182, miR-218-1, miR-29a, and miR-330) related to Parkinson's disease were identified, along with more microRNA targeted genes of interest like RIMS3, SEMA6D and SYNJ1. David and IPA enrichment analysis of KEGG and canonical pathways provided valuable mechanistic information emphasizing among others the role of chemokine signaling, adherence junction, and regulation of actin cytoskeleton pathways. Several routes for possible disease initiation and neuro protection mechanisms triggered via the extra-cellular ligands such as CX3CL1, SEMA6D and IL12B were thus uncovered, and a dual regulatory system of integrated transcription factors and microRNAs mechanisms was detected.
    04/2013; 7:e201304004. DOI:10.5936/csbj.201304004
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Abnormal phosphorylation of the microtubule-associated protein tau in neurodegenerative disorders, including Alzheimer's disease (AD) and frontotemporal lobar degeneration, is associated with disrupted axonal transport and synaptic dysfunction ultimately manifesting as histopathological lesions of protein aggregates. Glycogen synthase kinase 3β (GSK3β) may be critical for the pathological hyperphosphorylation of tau. Here, we examined the role of the proteasome-associated protein Nedd8 ultimate buster 1 (NUB1) in the neuropathogenic phosphorylation and aggregation of tau. We reveal that NUB1 interacted with both tau and GSK3β to disrupt their interaction, and abolished recruitment of GSK3β to tau inclusions. Moreover, NUB1 reduced GSK3β-mediated phosphorylation of tau and aggregation of tau in intracellular inclusions. Strikingly, NUB1 induced GSK3β degradation. Deletion of the NUB1 ubiquitin-like (UBL) domain did not impair the interaction with tau and GSK3β, and the ability to suppress the phosphorylation and aggregation of tau was not affected. However, the UBL motif was necessary for GSK3β degradation. Deletion of the NUB1 ubiquitin-associated (UBA) domain abrogated the ability of NUB1 to interact with and degrade GSK3β. Moreover, the UBA domain was required to suppress the aggregation of tau. Silencing of NUB1 in cells stabilized endogenous GSK3β and exacerbated tau phosphorylation. Thus, we propose that NUB1, by regulating GSK3β levels, modulates tau phosphorylation and aggregation, and is a key player in neurodegeneration associated with tau pathology. Moreover, NUB1 regulation of GSK3β could modulate numerous signalling pathways in which GSK3β is a centrally important effector.
    Human Molecular Genetics 09/2012; DOI:10.1093/hmg/dds376 · 6.68 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Accumulating evidence implicates impairment of the autophagy-lysosome pathway in Alzheimer's disease (AD). Recently discovered, transcription factor EB (TFEB) is a molecule shown to play central roles in cellular degradative processes. Here we investigate the role of TFEB in AD mouse models. In this study, we demonstrate that TFEB effectively reduces neurofibrillary tangle pathology and rescues behavioral and synaptic deficits and neurodegeneration in the rTg4510 mouse model of tauopathy with no detectable adverse effects when expressed in wild-type mice. TFEB specifically targets hyperphosphorylated and misfolded Tau species present in both soluble and aggregated fractions while leaving normal Tau intact. We provide in vitro evidence that this effect requires lysosomal activity and we identify phosphatase and tensin homolog (PTEN) as a direct target of TFEB that is required for TFEB-dependent aberrant Tau clearance. The specificity and efficacy of TFEB in mediating the clearance of toxic Tau species makes it an attractive therapeutic target for treating diseases of tauopathy including AD.
    EMBO Molecular Medicine 07/2014; DOI:10.15252/emmm.201303671 · 8.25 Impact Factor

Preview (2 Sources)

Download
0 Downloads
Available from