Two pathologically confirmed cases of novel mutations in the MAPT gene causing frontotemporal dementia

Shafei, Rachelle; Woollacott, Ione O.C.; Mummery, Catherine J.; Bocchetta, Martina; Guerreiro, Rita; Brás, José; Warren, Jason D.; Lashley, Tammaryn; Jaunmuktane, Zane; Rohrer, Jonathan D.

doi:10.1016/j.neurobiolaging.2019.11.009

Cited by 6 publications

(4 citation statements)

References 25 publications

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“…Indeed, mutations in exons 9–13 (K257T, L266V, G272V, G273R, S305N, L315R, S320F, S320Y, P332S, Q336H, Q336R, K369I, E372G and G389) were associated with 3R tauopathies, such as PiD [ 17 , 104 ] ( ) (accessed on 17 January 2022). Recently, a deletion from G389 to I392 was also described as predominant in 3R tauopathy [ 105 ]. However, the most characteristic MAPT mutations affect the alternative splicing by inclusion of exon 10, resulting in the overproduction of 4R Tau.…”

Section: Tau Protein Metabolismmentioning

confidence: 99%

Tau mRNA Metabolism in Neurodegenerative Diseases: A Tangle Journey

et al. 2022

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Tau proteins are known to be mainly involved in regulation of microtubule dynamics. Besides this function, which is critical for axonal transport and signal transduction, tau proteins also have other roles in neurons. Moreover, tau proteins are turned into aggregates and consequently trigger many neurodegenerative diseases termed tauopathies, of which Alzheimer’s disease (AD) is the figurehead. Such pathological aggregation processes are critical for the onset of these diseases. Among the various causes of tau protein pathogenicity, abnormal tau mRNA metabolism, expression and dysregulation of tau post-translational modifications are critical steps. Moreover, the relevance of tau function to general mRNA metabolism has been highlighted recently in tauopathies. In this review, we mainly focus on how mRNA metabolism impacts the onset and development of tauopathies. Thus, we intend to portray how mRNA metabolism of, or mediated by, tau is associated with neurodegenerative diseases.

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Section: Tau Protein Metabolismmentioning

confidence: 99%

Tau mRNA Metabolism in Neurodegenerative Diseases: A Tangle Journey

et al. 2022

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“…MAPT mutations were first reported in families of frontotemporal dementia (FTD) and parkinsonism linked to chromosome 17 (FTDP-17) in 1998 [ 26 ]. Since then, more than 60 mutations in MAPT have been identified, mostly characterized by behavioural changes and/or clinical parkinsonism [ 27 ]. MAPT is involved in a series of neurodegenerative disorders [ 28 ] and the case-control GWAS of PSP has identified that MAPT is the risk locus with the strongest effect size [ 19 ].…”

Section: Single-gene Mutations Associated With Pspmentioning

confidence: 99%

Genetics of Progressive Supranuclear Palsy: A Review

Wen

Zhou

Jiao

et al. 2021

JPD

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Progressive supranuclear palsy (PSP) is an atypical parkinsonism with prominent 4R-tau neuropathology, and the classical clinical phenotype is characterized by vertical supranuclear gaze palsy, unprovoked falls, akinetic-rigid syndrome and cognitive decline. Though PSP is generally regarded as sporadic, there is increasing evidence suggesting that a series of common and rare genetic variants impact on sporadic and familial forms of PSP. To date, more than 10 genes have been reported to show a potential association with PSP. Among these genes, the microtubule-associated protein tau (MAPT) is the risk locus with the strongest effect size on sporadic PSP in the case-control genome-wide association studies (GWAS). Additionally, MAPT mutations are the most common cause of familial PSP while the leucine-rich repeat kinase 2 (LRRK2) is a rare monogenic cause of PSP, and several other gene mutations may mimic the PSP phenotype, like the dynactin subunit 1 (DCTN1). In total, 15 MAPT mutations have been identified in cases with PSP, and the mean age at onset is much earlier than in cases carrying LRRK2 or DCTN1 mutations. GWAS have further identified several risk loci of PSP, proposing molecular pathways related to PSP. The present review focused on genetic studies on PSP and summarized genetic factors of PSP, which may help to elucidate the underlying pathogenesis and provide new perspectives for therapeutic strategies.

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“…Eventually, p-tau aggregates to form paired helical filaments (PHF), which bundle to form the intracellular NFTs seen in the postmortem pathology of AD [105]. PHF are not characteristic of only AD and have been characterized in frontotemporal dementia (FTD) linked to a V337M MAPT mutation as well as D252V and G389_I392del mutations [106,107]. These mutations and subsequent phenotypes demonstrate that MAPs play an important role in regulating intracellular activity in neurons found in various regions of not only the hippocampus but also the cerebral cortex.…”

Section: Pathology Of Admentioning

confidence: 99%

The Potential of Induced Pluripotent Stem Cells to Treat and Model Alzheimer’s Disease

Schulz

2021

Stem Cells International

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An estimated 6.2 million Americans aged 65 or older are currently living with Alzheimer’s disease (AD), a neurodegenerative disease that disrupts an individual’s ability to function independently through the degeneration of key regions in the brain, including but not limited to the hippocampus, the prefrontal cortex, and the motor cortex. The cause of this degeneration is not known, but research has found two proteins that undergo posttranslational modifications: tau, a protein concentrated in the axons of neurons, and amyloid precursor protein (APP), a protein concentrated near the synapse. Through mechanisms that have yet to be elucidated, the accumulation of these two proteins in their abnormal aggregate forms leads to the neurodegeneration that is characteristic of AD. Until the invention of induced pluripotent stem cells (iPSCs) in 2006, the bulk of research was carried out using transgenic animal models that offered little promise in their ability to translate well from benchtop to bedside, creating a bottleneck in the development of therapeutics. However, with iPSC, patient-specific cell cultures can be utilized to create models based on human cells. These human cells have the potential to avoid issues in translatability that have plagued animal models by providing researchers with a model that closely resembles and mimics the neurons found in humans. By using human iPSC technology, researchers can create more accurate models of AD ex vivo while also focusing on regenerative medicine using iPSC in vivo. The following review focuses on the current uses of iPSC and how they have the potential to regenerate damaged neuronal tissue, in the hopes that these technologies can assist in getting through the bottleneck of AD therapeutic research.

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Two pathologically confirmed cases of novel mutations in the MAPT gene causing frontotemporal dementia

Cited by 6 publications

References 25 publications

Tau mRNA Metabolism in Neurodegenerative Diseases: A Tangle Journey

Tau mRNA Metabolism in Neurodegenerative Diseases: A Tangle Journey

Genetics of Progressive Supranuclear Palsy: A Review

The Potential of Induced Pluripotent Stem Cells to Treat and Model Alzheimer’s Disease

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