Altered Levels and Isoforms of Tau and Nuclear Membrane Invaginations in Huntington’s Disease

Fernández‐Nogales, Marta; Lucas, José J.

doi:10.3389/fncel.2019.00574

Cited by 27 publications

(24 citation statements)

References 130 publications

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“…Tau phosphorylation is increased in vulnerable regions of the brains of HD mice and patients where it accumulates in aggregates [ 92 , 93 , 94 , 95 , 96 ]. Additionally, and as a result of splicing alterations, the expression levels of specific Tau isoforms are changed in HD brain tissue causing disruption of the nuclear membrane [ 97 , 98 ]. Based on the documented Tau pathology in HD several investigators have referred to HD as a tauopathy, placing it in the same disease category as AD [ 99 , 100 , 101 , 102 ].…”

Section: The Diseasesmentioning

confidence: 99%

When Good Kinases Go Rogue: GSK3, p38 MAPK and CDKs as Therapeutic Targets for Alzheimer’s and Huntington’s Disease

D’Mello¹

2021

IJMS

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Alzheimer’s disease (AD) is a mostly sporadic brain disorder characterized by cognitive decline resulting from selective neurodegeneration in the hippocampus and cerebral cortex whereas Huntington’s disease (HD) is a monogenic inherited disorder characterized by motor abnormalities and psychiatric disturbances resulting from selective neurodegeneration in the striatum. Although there have been numerous clinical trials for these diseases, they have been unsuccessful. Research conducted over the past three decades by a large number of laboratories has demonstrated that abnormal actions of common kinases play a key role in the pathogenesis of both AD and HD as well as several other neurodegenerative diseases. Prominent among these kinases are glycogen synthase kinase (GSK3), p38 mitogen-activated protein kinase (MAPK) and some of the cyclin-dependent kinases (CDKs). After a brief summary of the molecular and cell biology of AD and HD this review covers what is known about the role of these three groups of kinases in the brain and in the pathogenesis of the two neurodegenerative disorders. The potential of targeting GSK3, p38 MAPK and CDKS as effective therapeutics is also discussed as is a brief discussion on the utilization of recently developed drugs that simultaneously target two or all three of these groups of kinases. Multi-kinase inhibitors either by themselves or in combination with strategies currently being used such as immunotherapy or secretase inhibitors for AD and knockdown for HD could represent a more effective therapeutic approach for these fatal neurodegenerative diseases.

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Section: The Diseasesmentioning

confidence: 99%

When Good Kinases Go Rogue: GSK3, p38 MAPK and CDKs as Therapeutic Targets for Alzheimer’s and Huntington’s Disease

D’Mello¹

2021

IJMS

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“…The presence of Tau in the nuclear compartment was first described in the 1990s in neuroblastoma cells and in human brains [ 73 , 105 ]. It is still unclear how Tau is transported to the nucleus; however, it interacts directly with proteins of the Nuclear Pore Complex (NPC) and has been recently demonstrated to interact with TRIM28, a protein involved in transcriptional regulation and chromatin remodelling, which is able to shuttle Tau to the nucleus [ 106 , 107 , 108 ]. Concomitant Tau and TRIM28 increased levels have been measured in neuronal nuclei of AD human brains supporting their close dependence in nuclear transport and suggesting a pathological involvement of Tau in chromatin remodelling [ 108 ].…”

Section: Tau Functions In the Nuclear Compartment And Pathological Impact On Synaptic Functionsmentioning

confidence: 99%

Non-Canonical Roles of Tau and Their Contribution to Synaptic Dysfunction

Siano

Falcicchia

Origlia

et al. 2021

IJMS

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Tau plays a central role in a group of neurodegenerative disorders collectively named tauopathies. Despite the wide range of diverse symptoms at the onset and during the progression of the pathology, all tauopathies share two common hallmarks, namely the misfolding and aggregation of Tau protein and progressive synaptic dysfunctions. Tau aggregation correlates with cognitive decline and behavioural impairment. The mechanistic link between Tau misfolding and the synaptic dysfunction is still unknown, but this correlation is well established in the human brain and also in tauopathy mouse models. At the onset of the pathology, Tau undergoes post-translational modifications (PTMs) inducing the detachment from the cytoskeleton and its release in the cytoplasm as a soluble monomer. In this condition, the physiological enrichment in the axon is definitely disrupted, resulting in Tau relocalization in the cell soma and in dendrites. Subsequently, Tau aggregates into toxic oligomers and amyloidogenic forms that disrupt synaptic homeostasis and function, resulting in neuronal degeneration. The involvement of Tau in synaptic transmission alteration in tauopathies has been extensively reviewed. Here, we will focus on non-canonical Tau functions mediating synapse dysfunction.

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“…MAP2A and MAP2B are predominantly localized in the cell bodies and dendrites of mature neurons [ 53 ] while tau propagates mainly in axons [ 54 ] and dendrites [ 55 ]. Unlike other MT-associated proteins, the role of tau protein in the development of pathology in the brain of some patients with Huntington’s disease (HD) is clear [ 56 ], while the role of mHTT in the disease progress is not known [ 57 , 58 , 59 ].…”

Section: The Role Of Endogenous Mt Modulators and Tubulin Post-tramentioning

confidence: 99%

Huntington’s Disease—An Outlook on the Interplay of the HTT Protein, Microtubules and Actin Cytoskeletal Components

Taran

Shuvalova

Lagarkova

et al. 2020

Cells

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Huntington’s disease is a severe and currently incurable neurodegenerative disease. An autosomal dominant mutation in the Huntingtin gene (HTT) causes an increase in the polyglutamine fragment length at the protein N-terminus. The consequence of the mutation is the death of neurons, mostly striatal neurons, leading to the occurrence of a complex of motor, cognitive and emotional-volitional personality sphere disorders in carriers. Despite intensive studies, the functions of both mutant and wild-type huntingtin remain poorly understood. Surprisingly, there is the selective effect of the mutant form of HTT even on nervous tissue, whereas the protein is expressed ubiquitously. Huntingtin plays a role in cell physiology and affects cell transport, endocytosis, protein degradation and other cellular and molecular processes. Our experimental data mining let us conclude that a significant part of the Huntingtin-involved cellular processes is mediated by microtubules and other cytoskeletal cell structures. The review attempts to look at unresolved issues in the study of the huntingtin and its mutant form, including their functions affecting microtubules and other components of the cell cytoskeleton.

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Altered Levels and Isoforms of Tau and Nuclear Membrane Invaginations in Huntington’s Disease

Cited by 27 publications

References 130 publications

When Good Kinases Go Rogue: GSK3, p38 MAPK and CDKs as Therapeutic Targets for Alzheimer’s and Huntington’s Disease

When Good Kinases Go Rogue: GSK3, p38 MAPK and CDKs as Therapeutic Targets for Alzheimer’s and Huntington’s Disease

Non-Canonical Roles of Tau and Their Contribution to Synaptic Dysfunction

Huntington’s Disease—An Outlook on the Interplay of the HTT Protein, Microtubules and Actin Cytoskeletal Components

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