Contribution of Tau Pathology to Mitochondrial Impairment in Neurodegeneration

Pérez, Marı́a José; Jara, Claudia; Quintanilla, Rodrigo A.

doi:10.3389/fnins.2018.00441

Cited by 108 publications

(90 citation statements)

References 132 publications

(202 reference statements)

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“…Various τ species have been shown to incite mitochondrial insult. For example, either phosphorylated τ or truncated τ forms disrupt mitochondrial membrane potential, cause oxidative stress, and hinder the calcium buffering capacity of the cell (Pérez, Jara, & Quintanilla, 2018). Moreover, truncated τ provokes mitochondrial dysfunction in vitro (Quintanilla, Matthews-Roberson, Dolan, & Johnson, 2009).…”

Section: Classical Ad Targets and Their Link To Mitochondrial Dysfumentioning

confidence: 99%

Mitochondrial dysfunction in Alzheimer's disease: Role in pathogenesis and novel therapeutic opportunities

Ortiz

Swerdlow

2019

British J Pharmacology

317

178

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Dysfunction of cell bioenergetics is a common feature of neurodegenerative diseases, the most common of which is Alzheimer's disease (AD). Disrupted energy utilization implicates mitochondria at its nexus. This review summarizes some of the evidence that points to faulty mitochondrial function in AD and highlights past and current therapeutic development efforts. Classical neuropathological hallmarks of disease (β‐amyloid and τ) and sporadic AD risk genes (APOE) may trigger mitochondrial disturbance, yet mitochondrial dysfunction may incite pathology. Preclinical and clinical efforts have overwhelmingly centred on the amyloid pathway, but clinical trials have yet to reveal clear‐cut benefits. AD therapies aimed at mitochondrial dysfunction are few and concentrate on reversing oxidative stress and cell death pathways. Novel research efforts aimed at boosting mitochondrial and bioenergetic function offer an alternative treatment strategy. Enhancing cell bioenergetics in preclinical models may yield widespread favourable effects that could benefit persons with AD. Linked Articles This article is part of a themed section on Therapeutics for Dementia and Alzheimer's Disease: New Directions for Precision Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.18/issuetoc

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Section: Classical Ad Targets and Their Link To Mitochondrial Dysfumentioning

confidence: 99%

Mitochondrial dysfunction in Alzheimer's disease: Role in pathogenesis and novel therapeutic opportunities

Ortiz

Swerdlow

2019

British J Pharmacology

317

178

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“…Mounting evidence highlights the dysfunction of mitochondria in tauopathies, including reduced bioenergetics as well as abnormal mitochondrial morphology [ 6 , 7 ]. Besides, abnormal tau has many effects on other cellular functions that may lead to neurodegeneration, which are nicely reviewed elsewhere [ 8 , 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

Insights into Disease-Associated Tau Impact on Mitochondria

Szabo

Eckert

Grimm

2020

IJMS

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Abnormal tau protein aggregation in the brain is a hallmark of tauopathies, such as frontotemporal lobar degeneration and Alzheimer’s disease. Substantial evidence has been linking tau to neurodegeneration, but the underlying mechanisms have yet to be clearly identified. Mitochondria are paramount organelles in neurons, as they provide the main source of energy (adenosine triphosphate) to these highly energetic cells. Mitochondrial dysfunction was identified as an early event of neurodegenerative diseases occurring even before the cognitive deficits. Tau protein was shown to interact with mitochondrial proteins and to impair mitochondrial bioenergetics and dynamics, leading to neurotoxicity. In this review, we discuss in detail the different impacts of disease-associated tau protein on mitochondrial functions, including mitochondrial transport, network dynamics, mitophagy and bioenergetics. We also give new insights about the effects of abnormal tau protein on mitochondrial neurosteroidogenesis, as well as on the endoplasmic reticulum-mitochondria coupling. A better understanding of the pathomechanisms of abnormal tau-induced mitochondrial failure may help to identify new targets for therapeutic interventions.

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“…Notably, higher p-tau levels have been shown to elongate the mitochondria as a result of delocalization of dynamin related protein 1 (DRP1), the fission protein for mitochondria. 19 Having in mind the decreased levels of p-tau in the fibroblast culture of the affected individual, we speculated that reduced p-tau could result in shorter or smaller mitochondria. Thus, we analyzed the effect of decreased TAO1 kinase levels on the integrity of the mitochondrial network by calculating the form factor in fibroblasts of a TAOK1 mutation carrier and two unrelated healthy controls (Figure 2E).…”

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confidence: 99%

De Novo Variants in TAOK1 Cause Neurodevelopmental Disorders

Dulovic-Mahlow

Trinh

Kandaswamy

et al. 2019

The American Journal of Human Genetics

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De novo variants represent a significant cause of neurodevelopmental delay and intellectual disability. A genetic basis can be identified in only half of individuals who have neurodevelopmental disorders (NDDs); this indicates that additional causes need to be elucidated. We compared the frequency of de novo variants in patient-parent trios with (n ¼ 2,030) versus without (n ¼ 2,755) NDDs. We identified de novo variants in TAOK1 (thousand and one [TAO] amino acid kinase 1), which encodes the serine/threonine-protein kinase TAO1, in three individuals with NDDs but not in persons who did not have NDDs. Through further screening and the use of GeneMatcher, five additional individuals with NDDs were found to have de novo variants. All eight variants were absent from gnomAD (Genome Aggregation Database). The variant carriers shared a non-specific phenotype of developmental delay, and six individuals had additional muscular hypotonia. We established a fibroblast line of one mutation carrier, and we demonstrated that reduced mRNA levels of TAOK1 could be increased upon cycloheximide treatment. These results indicate nonsense-mediated mRNA decay. Further, there was neither detectable phosphorylated TAO1 kinase nor phosphorylated tau in these cells, and mitochondrial morphology was altered. Knockdown of the ortholog gene Tao1 (Tao, CG14217) in Drosophila resulted in delayed early development. The majority of the Tao1-knockdown flies did not survive beyond the third instar larval stage. When compared to control flies, Tao1 knockdown flies revealed changed morphology of the ventral nerve cord and the neuromuscular junctions as well as a decreased number of endings (boutons). Furthermore, mitochondria in mutant flies showed altered distribution and decreased size in axons of motor neurons. Thus, we provide compelling evidence that de novo variants in TAOK1 cause NDDs.

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Contribution of Tau Pathology to Mitochondrial Impairment in Neurodegeneration

Cited by 108 publications

References 132 publications

Mitochondrial dysfunction in Alzheimer's disease: Role in pathogenesis and novel therapeutic opportunities

Mitochondrial dysfunction in Alzheimer's disease: Role in pathogenesis and novel therapeutic opportunities

Insights into Disease-Associated Tau Impact on Mitochondria

De Novo Variants in TAOK1 Cause Neurodevelopmental Disorders

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