Cdk5-mediated mitochondrial fission: A key player in dopaminergic toxicity in Huntington's disease

Cherubini, Marta; Puigdellívol, Mar; Alberch, Jordi; Ginés, Sílvia

doi:10.1016/j.bbadis.2015.06.025

Cited by 33 publications

(23 citation statements)

References 58 publications

(63 reference statements)

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“…Cdk5 phosphorylation of Drp1 also occurs in models of neurodegenerative disorders. Cdk5‐mediated phosphorylation of Drp1 can promote fission and apoptosis in striatal neurons that express mutant Huntington, an event that can be exacerbated by the addition of dopamine . This study implicates Cdk5‐Drp1 activation as a component of Huntington disease.…”

Section: Other Kinases Associated With Ommmentioning

confidence: 67%

Phosphoregulation on mitochondria: Integration of cell and organelle responses

2019

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Mitochondria are highly integrated organelles that are crucial to cell adaptation and mitigating adverse physiology. Recent studies demonstrate that fundamental signal transduction pathways incorporate mitochondrial substrates into their biological programs. Reversible phosphorylation is emerging as a useful mechanism to modulate mitochondrial function in accordance with cellular changes. Critical serine/threonine protein kinases, such as the c‐Jun N‐terminal kinase (JNK), protein kinase A (PKA), PTEN‐induced kinase‐1 (PINK1), and AMP‐dependent protein kinase (AMPK), readily translocate to the outer mitochondrial membrane (OMM), the interface of mitochondria‐cell communication. OMM protein kinases phosphorylate diverse mitochondrial substrates that have discrete effects on organelle dynamics, protein import, respiratory complex activity, antioxidant capacity, and apoptosis. OMM phosphorylation events can be tempered through the actions of local protein phosphatases, such as mitogen‐activated protein kinase phosphatase‐1 (MKP‐1) and protein phosphatase 2A (PP2A), to regulate the extent and duration of signaling. The central mediators of OMM signal transduction are the scaffold proteins because the relative abundance of these accessory proteins determines the magnitude and duration of a signaling event on the mitochondrial surface, which dictates the biological outcome of a local signal transduction pathway. The concentrations of scaffold proteins, such as A‐kinase anchoring proteins (AKAPs) and Sab (or SH3 binding protein 5—SH3BP5), have been shown to influence neuronal survival and vulnerability, respectively, in models of Parkinson's disease (PD), highlighting the importance of OMM signaling to health and disease. Despite recent progress, much remains to be discovered concerning the mechanisms of OMM signaling. Nonetheless, enhancing beneficial OMM signaling events and inhibiting detrimental protein‐protein interactions on the mitochondrial surface may represent highly selective approaches to restore mitochondrial health and homeostasis and mitigate organelle dysfunction in conditions such as PD.

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Section: Other Kinases Associated With Ommmentioning

confidence: 67%

Phosphoregulation on mitochondria: Integration of cell and organelle responses

2019

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“…In the case of HD, it is striatal medium spiny neurons that are preferentially lost. Although the basis for this selective vulnerability is unknown, certain studies have found that striatal neurons are prone to mitochondrial fragmentation, due to increased expression of the Drp1 receptor Fis1 (43), a pro-fission effect of dopaminergic signaling (40), or increased S-nitrosylation of Drp-1 (41). Thus, in HD, the energy demands of medium spiny neurons, together with a predisposition to fragmentation of the mitochondrial network, may explain why PPARδ transcription interference contributes to HD pathogenesis, and why PPARδ promotion of mitochondrial fusion in HD is neuroprotective.…”

Section: Discussionmentioning

confidence: 99%

PPARδ activation by bexarotene promotes neuroprotection by restoring bioenergetic and quality control homeostasis

et al. 2017

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Neurons must maintain protein and mitochondrial quality control for optimal function, an energetically expensive process. The PPARs are ligand-activated transcription factors that promote mitochondrial biogenesis and oxidative metabolism. We recently determined that transcriptional dysregulation of PPARδ contributes to Huntington’s disease (HD), a progressive neurodegenerative disorder resulting from a CAG-polyglutamine repeat expansion in the huntingtin gene. We documented that the PPARδ agonist KD3010 is an effective therapy for HD in a mouse model. PPARδ forms a heterodimer with the retinoid X receptor (RXR), and RXR agonists are capable of promoting PPARδ activation. One compound with potent RXR agonist activity is the FDA-approved drug bexarotene. Here, we tested the therapeutic potential of bexarotene in HD, and found that bexarotene was neuroprotective in cellular models of HD, including medium spiny-like neurons generated from induced pluripotent stem cells (iPSCs) derived from patients with HD. To evaluate bexarotene as a treatment for HD, we treated the N171-82Q mouse model with the drug and found that bexarotene improved motor function, reduced neurodegeneration, and increased survival. To determine the basis for PPARδ neuroprotection, we evaluated metabolic function and noted markedly impaired oxidative metabolism in HD neurons, which was rescued by bexarotene or KD3010. We examined mitochondrial and protein quality control in cellular models of HD, and observed that treatment with a PPARδ agonist promoted cellular quality control. By boosting cellular activities that are dysfunctional in HD, PPARδ activation may have therapeutic applications in HD and potentially other related neurodegenerative diseases.

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“…Based on the ROS-mediated CDK5 activation ( Sun et al, 2008 ) and the present data, our findings indicate that Nox-derived ROS may increase CDK5 activity and facilitate DRP1-mediated mitochondrial fission in PV cells. Indeed, inhibition of CDK5 activity abrogates the increase in mitochondrial fission by inhibiting DRP1 activity in Huntington’s disease model ( Cherubini et al, 2015 ) and NMDA-induced neuronal loss ( Jahani-Asl et al, 2015 ). The present data also reveal that roscovitine ameliorated SE-induced excessive mitochondrial fission.…”

Section: Discussionmentioning

confidence: 99%

p47Phox/CDK5/DRP1-Mediated Mitochondrial Fission Evokes PV Cell Degeneration in the Rat Dentate Gyrus Following Status Epilepticus

Kim

Kang

2017

Front. Cell. Neurosci.

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Parvalbumin (PV) is one of the calcium-binding proteins, which plays an important role in the responsiveness of inhibitory neurons to an adaptation to repetitive spikes. Furthermore, PV neurons are highly vulnerable to status epilepticus (SE, prolonged seizure activity), although the underlining mechanism remains to be clarified. In the present study, we found that p47Phox expression was transiently and selectively increased in PV neurons 6 h after SE. This up-regulated p47Phox expression was accompanied by excessive mitochondrial fission. In this time point, CDK5-tyrosine 15 and dynamin-related protein 1 (DRP1)-serine 616 phosphorylations were also increased in PV cells. Apocynin (a p47Phox inhibitor) effectively mitigated PV cell loss via inhibition of CDK5/DRP1 phosphorylations and mitochondrial fragmentation induced by SE. Roscovitine (a CDK5 inhibitor) and Mdivi-1 (a DRP1 inhibitor) attenuated SE-induced PV cell loss by inhibiting aberrant mitochondrial fission. These findings suggest that p47Phox/CDK5/DRP1 may be one of the important upstream signaling pathways in PV cell degeneration induced by SE via excessive mitochondrial fragmentation.

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Cdk5-mediated mitochondrial fission: A key player in dopaminergic toxicity in Huntington's disease

Cited by 33 publications

References 58 publications

Phosphoregulation on mitochondria: Integration of cell and organelle responses

Phosphoregulation on mitochondria: Integration of cell and organelle responses

PPARδ activation by bexarotene promotes neuroprotection by restoring bioenergetic and quality control homeostasis

p47Phox/CDK5/DRP1-Mediated Mitochondrial Fission Evokes PV Cell Degeneration in the Rat Dentate Gyrus Following Status Epilepticus

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