Huntington's disease is a four-repeat tauopathy with tau nuclear rods

Fernández‐Nogales, Marta; Cabrera, Jorge Rubén; Santos-Galindo, María; Hoozemans, Jeroen J. M.; Ferrer, Isidró; Rozemüller, Annemieke; Hernández, Félix; Ávila, Jesús; Lucas, José J.

doi:10.1038/nm.3617

Cited by 189 publications

(237 citation statements)

References 27 publications

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“…Through such convergent screens, we found that TRIM28 regulates the levels of both disease-driving proteins. Our finding that TRIM28 regulates α-Syn and tau by promoting their nuclear localization and accumulation dovetails nicely with studies indicating that altered cellular distribution of α-Syn and tau contributes to neurodegeneration (Fares et al, 2014; Fernández-Nogales et al, 2014; Kontopoulos et al, 2006). Indeed, several lines of evidence suggest that mislocalization or missorting of α-Syn and tau as a result of mutations, post-translational modification or overexpression, rather than their respective aggregation in the form of Lewy bodies and NFTs, are what promotes neurodegeneration (Frandemiche et al, 2014; Wilson et al, 2004).…”

Section: Discussionsupporting

confidence: 87%

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

Rousseaux

Haro

Lasagna‐Reeves

et al. 2016

eLife

106

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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Section: Discussionsupporting

confidence: 87%

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

Rousseaux

Haro

Lasagna‐Reeves

et al. 2016

eLife

106

117

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“…It might be expected that such an RNA toxicity based mechanism would have additional wide-spread consequences on global alternative splicing, similar to sequestration of MBNL1 in myotonic dystrophy. In fact, an unpublished study has identified various alternatively spliced transcripts in HD mouse model tissue (Gipson TA and Housman DE, unpublished data) and an increase of the 4R/3R tau mRNA ratio has been observed [59]. Intriguingly, we identified at least one module that was significantly enriched for genes involved in RNA binding/mRNA processing in all three brain region networks (Tables 1, 2 and 3), which had not been discovered in the original publication.…”

Section: Discussionmentioning

confidence: 99%

A common gene expression signature in Huntington’s disease patient brain regions

Neueder

Bates

2014

BMC Med Genomics

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BackgroundGene expression data provide invaluable insights into disease mechanisms. In Huntington’s disease (HD), a neurodegenerative disease caused by a tri-nucleotide repeat expansion in the huntingtin gene, extensive transcriptional dysregulation has been reported. Conventional dysregulation analysis has shown that e.g. in the caudate nucleus of the post mortem HD brain the gene expression level of about a third of all genes was altered. Owing to this large number of dysregulated genes, the underlying relevance of expression changes is often lost in huge gene lists that are difficult to comprehend.MethodsTo alleviate this problem, we employed weighted correlation network analysis to archival gene expression datasets of HD post mortem brain regions.ResultsWe were able to uncover previously unidentified transcription dysregulation in the HD cerebellum that contained a gene expression signature in common with the caudate nucleus and the BA4 region of the frontal cortex. Furthermore, we found that yet unassociated pathways, e.g. global mRNA processing, were dysregulated in HD. We provide evidence to show that, contrary to previous findings, mutant huntingtin is sufficient to induce a subset of stress response genes in the cerebellum and frontal cortex BA4 region. The comparison of HD with other neurodegenerative disorders showed that the immune system, in particular the complement system, is generally activated. We also demonstrate that HD mouse models mimic some aspects of the disease very well, while others, e.g. the activation of the immune system are inadequately reflected.ConclusionOur analysis provides novel insights into the molecular pathogenesis in HD and identifies genes and pathways as potential therapeutic targets.Electronic supplementary materialThe online version of this article (doi:10.1186/s12920-014-0060-2) contains supplementary material, which is available to authorized users.

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“…Tau repeat domains bind at the interface between α- and β-tubulin heterodimers, suggesting that there is competition between their physiological interaction with tubulin and pathogenic misfolding (Kadavath et al, 2015). Most recently, Huntington’s disease has been confirmed as 4R tauopathy (Fernández-Nogales et al, 2014). …”

Section: Clinical and Neuropathological Criteria For Ad Diagnosismentioning

confidence: 99%

Monoaminergic neuropathology in Alzheimer’s disease

Šimić

Leko

Wray³

et al. 2017

Progress in Neurobiology

230

142

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None of the proposed mechanisms of Alzheimer’s disease (AD) fully explains the distribution patterns of the neuropathological changes at the cellular and regional levels, and their clinical correlates. One aspect of this problem lies in the complex genetic, epigenetic, and environmental landscape of AD: early-onset AD is often familial with autosomal dominant inheritance, while the vast majority of AD cases are late-onset, with the ε4 variant of the gene encoding apolipoprotein E (APOE) known to confer a 5–20 fold increased risk with partial penetrance. Mechanisms by which genetic variants and environmental factors influence the development of AD pathological changes, especially neurofibrillary degeneration, are not yet known. Here we review current knowledge of the involvement of the monoaminergic systems in AD. The changes in the serotonergic, noradrenergic, dopaminergic, histaminergic, and melatonergic systems in AD are briefly described. We also summarize the possibilities for monoamine-based treatment in AD. Besides neuropathologic AD criteria that include the noradrenergic locus coeruleus (LC), special emphasis is given to the serotonergic dorsal raphe nucleus (DRN). Both of these brainstem nuclei are among the first to be affected by tau protein abnormalities in the course of sporadic AD, causing behavioral and cognitive symptoms of variable severity. The possibility that most of the tangle-bearing neurons of the LC and DRN may release amyloid β as well as soluble monomeric or oligomeric tau protein trans-synaptically by their diffuse projections to the cerebral cortex emphasizes their selective vulnerability and warrants further investigations of the monoaminergic systems in AD.

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Huntington's disease is a four-repeat tauopathy with tau nuclear rods

Cited by 189 publications

References 27 publications

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

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

A common gene expression signature in Huntington’s disease patient brain regions

Monoaminergic neuropathology in Alzheimer’s disease

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