The tau S305S mutation causes frontotemporal dementia with parkinsonism
ABSTRACT Members of families with mutations in the tau gene are known to be heterogeneous in their clinical presentation, ranging from frontotemporal dementia to a clinical picture more resembling corticobasal degeneration or progressive supranuclear palsy. In this report, we describe a new phenotype for the tau S305S mutation, previously described as progressive supranuclear palsy. Clinically, the three affected family members showed alterations in personality and behaviour as well as cognitive decline and late levodopa-resistant parkinsonian symptoms, consistent with the diagnosis of frontotemporal dementia with parkinsonism linked to chromosome 17. One autopsied case displayed degeneration of the frontal and temporal lobes together with extensive tau pathology in both neurones and glial cells. Sarkosyl-soluble and -insoluble tau extracted from frontal cortex revealed a ratio shift with decreased levels of tau with three microtubule-binding repeats and increased levels of tau with four microtubule-binding repeats (4R tau). These findings provide further evidence for the clinical and pathological variation both within and between families with mutations in the tau gene. In addition, they support previous studies which demonstrate that the S305S mutation influences the splicing of tau exon 10 and results in an overproduction of 4R tau.
- SourceAvailable from: Alberto Javier Espay
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- "It also tends to develop at a younger age, about a decade earlier, than in FTDP linked to chromosome 17 but with ubiquitin and TDP-43-positive pathology (FTDP-17U/PGRN) (Boeve and Hutton 2008). A number of MAPT mutations have been reported among those with early (N279K, delN296, S305S, +11) (Soliveri et al. 2003; Pastor et al. 2001; Wszolek et al. 2001; Skoglund et al. 2008) or late (P301S, N296H, +3, +12, +14, +16; Baba et al. 2007; Iseki et al. 2001; Rohrer et al. 2011) parkinsonism associated with FTLDP-17T/MAPT, with a picture most often resembling PSP. Similarly, several mutations in PGRN have been reported among those with parkinsonism associated with FTDP-17U/PGRN, with a phenotype most often suggestive of CBS, with or without language abnormalities (c.26C>A, g.2988_2989delCA, P439_R440fsX6, IVS1+1 G–>A, +1, +11; Wider et al. 2008; Gabryelewicz et al. 2010; Boeve et al. 2006). "
ABSTRACT: Frontotemporal dementia is commonly associated with parkinsonism in several sporadic (i.e., progressive supranuclear palsy, corticobasal degeneration) and familial neurodegenerative disorders (i.e., frontotemporal dementia associated with parkinsonism and MAPT or progranulin mutations in chromosome 17). The clinical diagnosis of these disorders may be challenging in view of overlapping clinical features, particularly in speech, language, and behavior. The motor and cognitive phenotypes can be viewed within a spectrum of clinical, pathologic, and genetic disorders with no discrete clinicopathologic correlations but rather lying within a dementia-parkinsonism continuum. Neuroimaging and cerebrospinal fluid analysis can be helpful, but the poor specificity of clinical and imaging features has enormously challenged the development of biological markers that could differentiate these disorders premortem. This gap is critical to bridge in order to allow testing of novel biological therapies that may slow the progression of these proteinopathies.Journal of Molecular Neuroscience 09/2011; 45(3):343-9. DOI:10.1007/s12031-011-9632-1 · 2.76 Impact Factor
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ABSTRACT: Microtubules are dysfunctional in a number of neurological and neuropsychiatric disorders, and there is evidence of their decreased stability. This article critically evaluates the feasibility of introducing microtubules with superior structural properties into dysfunctional brain areas to restore normal microtubule functions such as transport. Various approaches in biotechnology and nanotechnology exist that might be successful in this regard. One strategy is to design artificial tubulin genes, or DNA constructs, with specific point mutations that would subsequently (1) affect polymerization and depolymerization of microtubules, (2) alter posttranslational modifications, or (3) modify binding of microtubule-associated proteins—all in the direction of enhancing overall microtubule stability. Another strategy is to coat or functionalize the surface of microtubules, altering their properties in the direction of enhanced stability. The abnormal functioning of microtubules and their binding proteins is turning out to be a prominent defect found in separate neuronal populations of those diagnosed with Alzheimer's disease, Parkinson's disease, schizophrenia, or bipolar disorder. The current treatments for these disorders have met with varying degrees of success, and many of the treatments are associated with serious side effects. Nanotechnology and biotechnology can make significant contributions to the development of future treatments. DNA constructs for novel tubulins and nanoengineered "bionic" microtubules stand to vastly expand the biomedical arsenal of potential treatments aimed at repairing microtubules. Nonetheless, a great deal of research still needs to be done before such goals can be realized.Journal of Nanoneuroscience 05/2009; 1(1):85-94. DOI:10.1166/jns.2009.009
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ABSTRACT: A recent paradigm shift appears to be underway on what scientists believe to be the cause of Alzheimer's disease (AD). The amyloid hypothesis has dominated the field of basic research for the last 25 years, and although these massive efforts have culminated in efficient removal of amyloid from the brains of patients, the absence of beneficial effects for the patient have been greatly disappointing. This has created a shift in the focus on amyloid to a much greater focus on Tau protein, in the hope that preventing tangle formation may inhibit or delay the progression of AD. Although there are promising developments in this area of research, diversifying our efforts to identify novel early targets by understanding the upstream molecular mechanisms that lead to, or occur with, neurofibrillary tangle and plaque formation may provide more efficient therapies against AD. Among many areas in development, an emphasis on the role of caspase-6 (Casp6) activity in early neurodegenerative mechanisms brings hope of a novel target against AD. Casp6 activity is intimately associated with the pathologies that define AD, correlates well with lower cognitive performance in aged individuals, and is involved in axonal degeneration in several cellular and in vivo animal models. This is a review of the evidence showing the relevance of Casp6 activation as an early event that could be inhibited to prevent the progression of AD.European Journal of Neuroscience 06/2013; 37(12):2005-18. DOI:10.1111/ejn.12250 · 3.67 Impact Factor