Activation of the mitochondrial unfolded protein response promotes longevity and dopamine neuron survival in Parkinson’s disease models

Cooper, Jason; Machiela, Emily; Dues, Dylan J.; Spielbauer, Katie; Senchuk, Megan M.; Raamsdonk, Jeremy M. Van

doi:10.1038/s41598-017-16637-2

Cited by 84 publications

(70 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although the signals that disrupt MAMs and CORE are disputed 60 , it is likely that organelle-specific stress is a primary trigger. This primary trigger of organelle-specific stress is further corroborated with recent descriptions of a novel form of localized mitochondrial UPR (UPR mt ), which responds to excess ROS 59,61 .…”

Section: Discussionsupporting

confidence: 71%

Cross organelle stress response disruption promotes gentamicin-induced proteotoxicity

et al. 2020

View full text Add to dashboard Cite

Gentamicin is a nephrotoxic antibiotic that causes acute kidney injury (AKI) primarily by targeting the proximal tubule epithelial cell. The development of an effective therapy for gentamicin-induced renal cell injury is limited by incomplete mechanistic insight. To address this challenge, we propose that RNAi signal pathway screening could identify a unifying mechanism of gentamicin-induced cell injury and suggest a therapeutic strategy to ameliorate it. Computational analysis of RNAi signal screens in gentamicin-exposed human proximal tubule cells suggested the cross-organelle stress response (CORE), the unfolded protein response (UPR), and cell chaperones as key targets of gentamicin-induced injury. To test this hypothesis, we assessed the effect of gentamicin on the CORE, UPR, and cell chaperone function, and tested the therapeutic efficacy of enhancing cell chaperone content. Early gentamicin exposure disrupted the CORE, evidenced by a rise in the ATP:ADP ratio, mitochondrial-specific H 2 O 2 accumulation, Drp-1-mediated mitochondrial fragmentation, and endoplasmic reticulum-mitochondrial dissociation. CORE disruption preceded measurable increases in whole-cell oxidative stress, misfolded protein content, transcriptional UPR activation, and its untoward downstream effects: CHOP expression, PARP cleavage, and cell death. Geranylgeranylacetone, a therapeutic that increases cell chaperone content, prevented mitochondrial H 2 O 2 accumulation, preserved the CORE, reduced the burden of misfolded proteins and CHOP expression, and significantly improved survival in gentamicin-exposed cells. We identify CORE disruption as an early and remediable cause of gentamicin proteotoxicity that precedes downstream UPR activation and cell death. Preserving the CORE significantly improves renal cell survival likely by reducing organellespecific proteotoxicity during gentamicin exposure.

show abstract

Section: Discussionsupporting

confidence: 71%

Cross organelle stress response disruption promotes gentamicin-induced proteotoxicity

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Contrarily to data obtained in Drosophila, KO of the PINK1 gene in C. elegans does not cause any clear neurodegeneration (Cooper et al, 2017). Similarly, the loss of function of djr-1.2, the neuronal DJ-1 ortholog gene in C. elegans, does not induce any dopaminergic cell death (Cooper et al, 2017). Overall, most invertebrate genetic models of PD display significant neurodegeneration.…”

Section: Non-motor Deficitsmentioning

confidence: 90%

“…KO of pdr‐1, the C. elegans ortholog to the human Parkin gene, also induces a loss of dopaminergic neurons (Bornhorst, Chakraborty, Meyer, Lohren & Brinkhaus, ; Cooper, Machiela, Dues, Spielbauer & Senchuk, ; Springer, Hoppe, Schmidt & Baumeister, ). Contrarily to data obtained in Drosophila , KO of the PINK1 gene in C. elegans does not cause any clear neurodegeneration (Cooper et al., ). Similarly, the loss of function of djr‐1.2, the neuronal DJ‐1 ortholog gene in C. elegans , does not induce any dopaminergic cell death (Cooper et al., ).…”

Section: Neurodegeneration and Dopamine Depletionmentioning

confidence: 99%

“…Interestingly, overexpression of human WT or mutant LRKK2 protein (G2019S, R1441C) in C. elegans is associated with a drop in the levels of DA and DA transporters, which is more pronounced in transgenic organisms bearing the mutated forms of the gene (Table 7) (Saha, Guillily, Ferree, Lanceta & Chan, 2009;Yao et al, 2010). KO of pdr-1, the C. elegans ortholog to the human Parkin gene, also induces a loss of dopaminergic neurons (Bornhorst, Chakraborty, Meyer, Lohren & Brinkhaus, 2014;Cooper, Machiela, Dues, Spielbauer & Senchuk, 2017;Springer, Hoppe, Schmidt & Baumeister, 2005). Contrarily to data obtained in Drosophila, KO of the PINK1 gene in C. elegans does not cause any clear neurodegeneration (Cooper et al, 2017).…”

Section: Non-motor Deficitsmentioning

confidence: 99%

See 1 more Smart Citation

Genetically engineered animal models of Parkinson's disease: From worm to rodent

Breger

Fuzzati-Armentero²

2018

Eur J of Neuroscience

View full text Add to dashboard Cite

Parkinson's disease (PD) is a progressive neurological disorder characterised by aberrant accumulation of insoluble proteins, including alpha‐synuclein, and a loss of dopaminergic neurons in the substantia nigra. The extended neurodegeneration leads to a drop of striatal dopamine levels responsible for disabling motor and non‐motor impairments. Although the causes of the disease remain unclear, it is well accepted among the scientific community that the disorder may also have a genetic component. For that reason, the number of genetically engineered animal models has greatly increased over the past two decades, ranging from invertebrates to more complex organisms such as mice and rats. This trend is growing as new genetic variants associated with the disease are discovered. The EU Joint Programme – Neurodegenerative Disease Research (JPND) has promoted the creation of an online database aiming at summarising the different features of experimental models of Parkinson's disease. This review discusses available genetic models of PD and the extent to which they adequately mirror the human pathology and reflects on future development and uses of genetically engineered experimental models for the study of PD.

show abstract

“…It will be of interest to determine whether the tau mutants described here are perceived as stressors, and hence cause activation of a retrograde response, such as has been described previously for the C. elegans Nrf2 ortholog SKN-1 in adaptation to a decrease in mitophagy (84). Alternatively, other retrograde signaling pathways such as that mediated by ATFS-1 and the mitochondrial unfolded protein response (mtUPR) can also mediate adaptation to mitochondrial stress (85), including stress due to defects in mitophagy machinery (86). However, prolonged cellular activation of the mtUPR has been shown to be maladaptive in a C. elegans model of dopaminergic neurodegeneration (87), suggesting that ultimate role of stress response pathways is context dependent.…”

Section: Discussionmentioning

confidence: 99%

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

View full text Add to dashboard Cite

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...

show abstract

Activation of the mitochondrial unfolded protein response promotes longevity and dopamine neuron survival in Parkinson’s disease models

Cited by 84 publications

References 53 publications

Cross organelle stress response disruption promotes gentamicin-induced proteotoxicity

Cross organelle stress response disruption promotes gentamicin-induced proteotoxicity

Genetically engineered animal models of Parkinson's disease: From worm to rodent

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

Contact Info

Product

Resources

About