Dysfunctional Mitochondria and Mitophagy as Drivers of Alzheimer’s Disease Pathogenesis

Chakravorty, Anushka; Jetto, Cuckoo Teresa; Manjithaya, Ravi

doi:10.3389/fnagi.2019.00311

Cited by 146 publications

(112 citation statements)

References 191 publications

(246 reference statements)

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“…6). This observation is consistent with defective mitophagy being a prominent feature in age-related disorders (80), including AD (81), and contributing to premature aging such as observed in Werner’s syndrome patients and invertebrate Werner’s disease models (82). It is also particularly intriguing that the T231E and K274/281Q do not appear to exhibit the same age-dependence as Dendra2, TauT4, or T231A.…”

Section: Discussionsupporting

confidence: 84%

Alzheimer’s disease-relevant tau modifications selectively impact neurodegeneration and mitophagy in a novelC. eleganssingle-copy transgenic model

Guha

Fischer

Johnson

et al. 2020

Preprint

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21 Background: A defining pathological hallmark of the progressive neurodegenerative 22 disorder Alzheimer's disease (AD) is the accumulation of misfolded tau with abnormal 23 post-translational modifications (PTMs). These include phosphorylation at Threonine 231 24 (T231) and acetylation at Lysine 274 (K274) and at Lysine 281 (K281). Although tau is 25 recognized to play a central role in pathogenesis of AD, the precise mechanisms by which 26 these abnormal PTMs contribute to the neural toxicity of tau is unclear.27Methods: Human 0N4R tau (wild type) was expressed in touch receptor neurons of the 28 genetic model organism C. elegans through single-copy gene insertion. Defined 29 mutations were then introduced into the single-copy tau transgene through CRISPR-Cas9 30 genome editing. These mutations included T231E and T231A, to mimic phosphorylation 31 and phospho-ablation of a commonly observed pathological epitope, respectively, and 32 K274/281Q, to mimic disease-associated lysine acetylation. Stereotypical touch response 33 assays were used to assess behavioral defects in the transgenic strains as a function of 34 age, and genetically-encoded fluorescent biosensors were used to measure the 35 morphological dynamics and turnover of touch neuron mitochondria. 36Results: Unlike existing tau overexpression models, C. elegans single-copy expression 37 of tau did not elicit overt pathological phenotypes at baseline. However, strains 38 expressing disease associated PTM-mimetics (T231E and K274/281Q) exhibited 39 reduced touch sensation and morphological abnormalities that increased with age. In 40 addition, the PTM-mimetic mutants lacked the ability to engage mitophagy in response to 41 mitochondrial stress. 42 Conclusions: Limiting the expression of tau results in a genetic model where 43 pathological modifications and age result in evolving phenotypes, which may more closely 44 resemble the normal progression of AD. The finding that disease-associated PTMs 45 suppress compensatory responses to mitochondrial stress provides a new perspective 46 into the pathogenic mechanisms underlying AD. 47 modifications 49 BACKGROUND 50Alzheimer's disease (AD) is the most common degenerative brain disease in the aged 51 population. It is characterized by the progressive decline of cognition and memory, as 52 well as changes in behavior and personality (1). One of the key pathological hallmarks of 53 AD is neurofibrillary tangles (NFTs), which are primarily composed of abnormally modified 54 tau (2). Tau isolated from AD brain exhibits a number of posttranslational modifications 55 (PTMs); including increases in phosphorylation and acetylation at specific residues (3, 4). 56While it is clear that tau is central to AD pathogenesis, the concept of large insoluble NFTs 57 in AD and other tauopathies being the principle mediators of neuronal toxicity has been 58 gradually abandoned (5). Instead, toxicity appears to result from soluble or oligomeric 59 forms of tau that exhibit increased, disease-associated phosphorylation and acetylat...

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Section: Discussionsupporting

confidence: 84%

Alzheimer’s disease-relevant tau modifications selectively impact neurodegeneration and mitophagy in a novelC. eleganssingle-copy transgenic model

Guha

Fischer

Johnson

et al. 2020

Preprint

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“…In neuronal cells, this could result in cell death or a cell division signal, both of which are lethal [27,28]. It could also be possible that this condition in neuronal cells could lead to aggregation of misfolded proteins, creating an even worse neuronal intracellular environment [29]. Impaired autophagy might also be responsible for the decreased protein clearance and lipid imbalances in the neuronal cells of AD patients, resulting in lipid dyshomeostasis and disruption in the proteostasis network [30].…”

Section: Discussionmentioning

confidence: 99%

Tyramine and Amyloid Beta 42: A Toxic Synergy

Dhakal

Macreadie

2020

Biomedicines

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Implicated in various diseases including Parkinson’s disease, Huntington’s disease, migraines, schizophrenia and increased blood pressure, tyramine plays a crucial role as a neurotransmitter in the synaptic cleft by reducing serotonergic and dopaminergic signaling through a trace amine-associated receptor (TAAR1). There appear to be no studies investigating a connection of tyramine to Alzheimer’s disease. This study aimed to examine whether tyramine could be involved in AD pathology by using Saccharomyces cerevisiae expressing Aβ42. S. cerevisiae cells producing native Aβ42 were treated with different concentrations of tyramine, and the production of reactive oxygen species (ROS) was evaluated using flow cytometric cell analysis. There was dose-dependent ROS generation in wild-type yeast cells with tyramine. In yeast producing Aβ42, ROS levels generated were significantly higher than in controls, suggesting a synergistic toxicity of Aβ42 and tyramine. The addition of exogenous reduced glutathione (GSH) was found to rescue the cells with increased ROS, indicating depletion of intracellular GSH due to tyramine and Aβ42. Additionally, tyramine inhibited the respiratory growth of yeast cells producing GFP-Aβ42, while there was no growth inhibition when cells were producing GFP. Tyramine was also demonstrated to cause increased mitochondrial DNA damage, resulting in the formation of petite mutants that lack respiratory function. These findings indicate that there can be a detrimental synergy between Aβ42 and tyramine, which could be considered in Alzheimer’s disease. This work also demonstrates the utility of yeast as a model for studying toxic agents such as Aβ42, tyramine, and agents that might exacerbate AD pathology.

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“…Aβ-induced mitochondrial dysfunction has been extensively associated to AD pathology. This toxic effect would be mediated by a reduction in the electron transport chain enzymatic activities [186,187].…”

Section: Pathological Mechanisms Of β-Amyloid Peptide Aggregationmentioning

confidence: 99%

Proteotoxicity and Neurodegenerative Diseases

Ruz¹,

Alcantud²,

Montero³

et al. 2020

IJMS

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Neurodegenerative diseases are a major burden for our society, affecting millions of people worldwide. A main goal of past and current research is to enhance our understanding of the mechanisms underlying proteotoxicity, a common theme among these incurable and debilitating conditions. Cell proteome alteration is considered to be one of the main driving forces that triggers neurodegeneration, and unraveling the biological complexity behind the affected molecular pathways constitutes a daunting challenge. This review summarizes the current state on key processes that lead to cellular proteotoxicity in Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis, providing a comprehensive landscape of recent literature. A foundational understanding of how proteotoxicity affects disease etiology and progression may provide essential insight towards potential targets amenable of therapeutic intervention.

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Dysfunctional Mitochondria and Mitophagy as Drivers of Alzheimer’s Disease Pathogenesis

Cited by 146 publications

References 191 publications

Alzheimer’s disease-relevant tau modifications selectively impact neurodegeneration and mitophagy in a novelC. eleganssingle-copy transgenic model

Alzheimer’s disease-relevant tau modifications selectively impact neurodegeneration and mitophagy in a novelC. eleganssingle-copy transgenic model

Tyramine and Amyloid Beta 42: A Toxic Synergy

Proteotoxicity and Neurodegenerative Diseases

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