The role of tau in the pathological process and clinical expression of Huntington’s disease

Vuono, Romina; Winder‐Rhodes, Sophie; Silva, Rohan de; Cisbani, Giulia; Drouin‐Ouellet, Janelle; Spillantini, Maria Grazia; Cicchetti, Francesca; Barker, Roger A.

doi:10.1093/brain/awv107

Cited by 117 publications

(149 citation statements)

References 41 publications

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“…We have previously demonstrated that tau oligomers also act as the pathological species in the disease progression of progressive supranuclear palsy (PSP) patients 40. Moreover, tau oligomers have been identified in cortical and striatal brain regions in patients with other amyloid diseases, such as Huntington's disease 41. These observations further support testing the levels of tau oligomers in the CSF of other tauopathies as well as other neurodegenerative diseases.…”

Section: Discussionmentioning

confidence: 63%

Tau oligomers in cerebrospinal fluid in Alzheimer's disease

Sengupta

Portelius

Hansson

et al. 2017

Ann Clin Transl Neurol

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ObjectiveWith an increasing incidence of Alzheimer's disease (AD) and neurodegenerative tauopathies, there is an urgent need to develop reliable biomarkers for the diagnosis and monitoring of the disease, such as the recently discovered toxic tau oligomers. Here, we aimed to demonstrate the presence of tau oligomers in the cerebrospinal fluid (CSF) of patients with cognitive deficits, and to determine whether tau oligomers could serve as a potential biomarker for AD.MethodsA multicentric collaborative study involving a double‐blinded analysis with a total of 98 subjects with moderate to severe AD (N = 41), mild AD (N = 31), and nondemented control subjects (N = 26), and two pilot studies of 33 total patients with AD (N = 19) and control (N = 14) subjects were performed. We carried out biochemical assays to measure oligomeric tau from CSF of these patients with various degrees of cognitive impairment as well as cognitively normal controls.ResultsUsing a highly reproducible indirect ELISA method, we found elevated levels of tau oligomers in AD patients compared to age‐matched controls. Western blot analysis confirmed the presence of oligomeric forms of tau in CSF. In addition, the ratio of oligomeric to total tau increased in the order: moderate to severe AD, mild AD, and controls.ConclusionThese assays are suitable for the analysis of human CSF samples. These results here suggest that CSF tau oligomer measurements could be optimized and added to the panel of CSF biomarkers for the accurate and early detection of AD.

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Section: Discussionmentioning

confidence: 63%

Tau oligomers in cerebrospinal fluid in Alzheimer's disease

Sengupta

Portelius

Hansson

et al. 2017

Ann Clin Transl Neurol

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“…Other brain areas are also affected but less severely. In line with this, two splicing alterations have been described that may be important for the pathogenesis of HD; one in the HTT gene itself giving rise to a highly toxic N-terminal form of mutant HTT (27) and more recently, we and others have demonstrated missplicing of the MAP Tau exon 10 in HD patients (7,31). HD thus belongs to the group of CAG trinucleotide repeat/PolyQ disorders (22).…”

Section: Introductionmentioning

confidence: 65%

MAP2 Splicing is Altered in Huntington's Disease

Cabrera

Lucas

2016

Brain Pathology

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Dendritic alteration of striatal medium spiny neurons is one of the earliest morphological abnormalities in Huntington's disease (HD). The main microtubule-associated protein in dendrites is MAP2. The low-molecular weight isoforms of MAP2 (LMW-MAP2) are the juvenile forms resulting from exclusion of the sequence encoded by exons E7-E9 and are downregulated after the early stages of neuronal development when E7-E9 exon-including high-molecular weight isoforms (HMW-MAP2) are favored. Splicing alteration has recently been proposed to contribute to HD in view of two pathogenic missplicing events resulting in a highly toxic N-terminal version of mutant huntingtin and in a detrimental imbalance in MAP Tau isoforms with three or four tubulin-binding repeats. Both splicing events are postulated targets of the SR splicing factor SRSF6 which has recently been reported to be dramatically altered in HD. SR proteins often regulate functionally related sets of genes and SRSF6 targets are enriched in genes involved in brain organogenesis including several actin-and tubulin-binding proteins. Here we hypothesized that MAP2 might be target of SRSF6 and altered in HD. By SRSF6 knockdown in neuroblastoma cells, we demonstrate that splicing of MAP2 E7-E9 exons is affected by SRSF6. We then show a disbalance in LMW and HMW MAP2 mRNA isoforms in HD striatum in favor of the juvenile LMW forms together with a decrease in total MAP2 mRNA. This is accompanied by a global decrease in total MAP2 protein due to almost total disappearance of HMW-MAP2 isoforms with preservation of LMW-MAP2 isoforms. Accordingly, the predominant dendritic MAP2 staining in striatal neuropil of control subjects is absent in HD cases. In these, MAP2-immunoreactivity is faint and restricted to neuronal cell bodies often showing a sharp boundary at the base of dendrites. Together, our results highlight the importance of splicing alteration in HD and suggest that MAP2 alteration contributes to dendritic atrophy.

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“…Further, PD-causing mutations in α-Syn increase its nuclear accumulation (Fares et al, 2014; Kontopoulos et al, 2006). Moreover, postmortem studies of tissue from AD and Huntington disease patients indicate that misfolded tau accumulates in the nucleus of neurons in the form of rod-like deposits (Fernández-Nogales et al, 2014; Vuono et al, 2015). Our finding that TRIM28 drives the nuclear accumulation of α-Syn and tau provides new mechanistic insight into the steps that lead to the pathogenicity of these proteins and highlights a shared pathway for therapeutic targeting.…”

Section: Discussionmentioning

confidence: 99%

TRIM28 regulates the nuclear accumulation and toxicity of both alpha-synuclein and tau

Rousseaux

Haro

Lasagna‐Reeves

et al. 2016

eLife

100

117

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Several neurodegenerative diseases are driven by the toxic gain-of-function of specific proteins within the brain. Elevated levels of alpha-synuclein (α-Syn) appear to drive neurotoxicity in Parkinson's disease (PD); neuronal accumulation of tau is a hallmark of Alzheimer's disease (AD); and their increased levels cause neurodegeneration in humans and model organisms. Despite the clinical differences between AD and PD, several lines of evidence suggest that α-Syn and tau overlap pathologically. The connections between α-Syn and tau led us to ask whether these proteins might be regulated through a shared pathway. We therefore screened for genes that affect post-translational levels of α-Syn and tau. We found that TRIM28 regulates α-Syn and tau levels and that its reduction rescues toxicity in animal models of tau- and α-Syn-mediated degeneration. TRIM28 stabilizes and promotes the nuclear accumulation and toxicity of both proteins. Intersecting screens across comorbid proteinopathies thus reveal shared mechanisms and therapeutic entry points.DOI: http://dx.doi.org/10.7554/eLife.19809.001

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The role of tau in the pathological process and clinical expression of Huntington’s disease

Cited by 117 publications

References 41 publications

Tau oligomers in cerebrospinal fluid in Alzheimer's disease

Tau oligomers in cerebrospinal fluid in Alzheimer's disease

MAP2 Splicing is Altered in Huntington's Disease

TRIM28 regulates the nuclear accumulation and toxicity of both alpha-synuclein and tau

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