PINK1 Silencing Modifies Dendritic Spine Dynamics of Mouse Hippocampal Neurons

Hernández, C J; Báez-Becerra, C; Contreras-Zarate, Maria Jose; Arboleda, Humberto; Arboleda, Gonzálo

doi:10.1007/s12031-019-01385-x

Cited by 18 publications

(22 citation statements)

References 36 publications

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“…In the present study, we observed that PINK1 expression induces changes in the dendrite density of C4da sensory neurons, suggesting that PINK1 modulates the dynamic plasticity of sensory neurons. Recent studies have also shown that PINK1 regulates dendrite morphogenesis and neuronal plasticity [41,42]. Thus, the results from our group and others suggest that PINK1 is an important regulator of dendrite plasticity.…”

Section: Discussionsupporting

confidence: 73%

PINK1 alleviates thermal hypersensitivity in a paclitaxel-induced Drosophila model of peripheral neuropathy

Kim

Yoon

et al. 2020

PLoS ONE

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Paclitaxel is a representative anticancer drug that induces chemotherapy-induced peripheral neuropathy (CIPN), a common side effect that limits many anticancer chemotherapies. Although PINK1, a key mediator of mitochondrial quality control, has been shown to protect neuronal cells from various toxic treatments, the role of PINK1 in CIPN has not been investigated. Here, we examined the effect of PINK1 expression on CIPN using a recently established paclitaxel-induced peripheral neuropathy model in Drosophila larvae. We found that the class IV dendritic arborization (C4da) sensory neuron-specific expression of PINK1 significantly ameliorated the paclitaxel-induced thermal hyperalgesia phenotype. In contrast, knockdown of PINK1 resulted in an increase in thermal hypersensitivity, suggesting a critical role for PINK1 in sensory neuron-mediated thermal nociceptive sensitivity. Interestingly, analysis of the C4da neuron morphology suggests that PINK1 expression alleviates paclitaxel-induced thermal hypersensitivity by means other than preventing alterations in sensory dendrites in C4da neurons. We found that paclitaxel induces mitochondrial dysfunction in C4da neurons and that PINK1 expression suppressed the paclitaxel-induced increase in mitophagy in C4da neurons. These results suggest that PINK1 mitigates paclitaxel-induced sensory dendrite alterations and restores mitochondrial homeostasis in C4da neurons and that improvement in mitochondrial quality control could be a promising strategy for the treatment of CIPN.

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Section: Discussionsupporting

confidence: 73%

PINK1 alleviates thermal hypersensitivity in a paclitaxel-induced Drosophila model of peripheral neuropathy

Kim

Yoon

et al. 2020

PLoS ONE

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“…Like primary neurons expressing mutant LRRK2 , Pink1 knockout mice exhibit reduced dendritic arbors in midbrain, cortical and hippocampal neurons [ 81 , 105 , 106 ]. Older, but not young (6-month vs 2-month) Pink1 knockout mice exhibit increased excitatory neurotransmission, accompanied by increased neurotransmitter release on KCl stimulation without changes in protein expression of synaptic vesicle proteins syntaxin1a, Munc-18 or SNAP25 [ 107 ].…”

Section: Mitochondrial Calcium Dysregulation In Neurodegenerative Diseasesmentioning

confidence: 99%

Excitotoxicity, calcium and mitochondria: a triad in synaptic neurodegeneration

Verma

Lizama

Chu

2022

Transl Neurodegener

173

125

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Glutamate is the most commonly engaged neurotransmitter in the mammalian central nervous system, acting to mediate excitatory neurotransmission. However, high levels of glutamatergic input elicit excitotoxicity, contributing to neuronal cell death following acute brain injuries such as stroke and trauma. While excitotoxic cell death has also been implicated in some neurodegenerative disease models, the role of acute apoptotic cell death remains controversial in the setting of chronic neurodegeneration. Nevertheless, it is clear that excitatory synaptic dysregulation contributes to neurodegeneration, as evidenced by protective effects of partial N-methyl-D-aspartate receptor antagonists. Here, we review evidence for sublethal excitatory injuries in relation to neurodegeneration associated with Parkinson’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis and Huntington’s disease. In contrast to classic excitotoxicity, emerging evidence implicates dysregulation of mitochondrial calcium handling in excitatory post-synaptic neurodegeneration. We discuss mechanisms that regulate mitochondrial calcium uptake and release, the impact of LRRK2, PINK1, Parkin, beta-amyloid and glucocerebrosidase on mitochondrial calcium transporters, and the role of autophagic mitochondrial loss in axodendritic shrinkage. Finally, we discuss strategies for normalizing the flux of calcium into and out of the mitochondrial matrix, thereby preventing mitochondrial calcium toxicity and excitotoxic dendritic loss. While the mechanisms that underlie increased uptake or decreased release of mitochondrial calcium vary in different model systems, a common set of strategies to normalize mitochondrial calcium flux can prevent excitatory mitochondrial toxicity and may be neuroprotective in multiple disease contexts.

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“…Interestingly, the authors found changes in actin regulatory proteins RhoGAP29 and ROCK2 which were concurrent with changes in spine morphology. The changes in dendritic spines, showing increased thin density spines and reduced head size of stubby spines, may be a sign of presymptomatic changes that lead to neurodegeneration in PD [ 149 ]. In comparison, a Pink1 KO rat model showed nigral neurodegeneration with 50% dopaminergic cell loss, an increase in striatal dopamine and serotonin content and significant motor deficits [ 136 ].…”

Section: Pink1/parkin In Neurodegenerationmentioning

confidence: 99%

PINK1/PARKIN signalling in neurodegeneration and neuroinflammation

Quinn

Moreira

Ambrósio

et al. 2020

acta neuropathol commun

260

136

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Mutations in the PTEN-induced kinase 1 (PINK1) and Parkin RBR E3 ubiquitin-protein ligase (PARKIN) genes are associated with familial forms of Parkinson’s disease (PD). PINK1, a protein kinase, and PARKIN, an E3 ubiquitin ligase, control the specific elimination of dysfunctional or superfluous mitochondria, thus fine-tuning mitochondrial network and preserving energy metabolism. PINK1 regulates PARKIN translocation in impaired mitochondria and drives their removal via selective autophagy, a process known as mitophagy. As knowledge obtained using different PINK1 and PARKIN transgenic animal models is being gathered, growing evidence supports the contribution of mitophagy impairment to several human pathologies, including PD and Alzheimer’s diseases (AD). Therefore, therapeutic interventions aiming to modulate PINK1/PARKIN signalling might have the potential to treat these diseases. In this review, we will start by discussing how the interplay of PINK1 and PARKIN signalling helps mediate mitochondrial physiology. We will continue by debating the role of mitochondrial dysfunction in disorders such as amyotrophic lateral sclerosis, Alzheimer’s, Huntington’s and Parkinson’s diseases, as well as eye diseases such as age-related macular degeneration and glaucoma, and the causative factors leading to PINK1/PARKIN-mediated neurodegeneration and neuroinflammation. Finally, we will discuss PINK1/PARKIN gene augmentation possibilities with a particular focus on AD, PD and glaucoma.

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PINK1 Silencing Modifies Dendritic Spine Dynamics of Mouse Hippocampal Neurons

Cited by 18 publications

References 36 publications

PINK1 alleviates thermal hypersensitivity in a paclitaxel-induced Drosophila model of peripheral neuropathy

PINK1 alleviates thermal hypersensitivity in a paclitaxel-induced Drosophila model of peripheral neuropathy

Excitotoxicity, calcium and mitochondria: a triad in synaptic neurodegeneration

PINK1/PARKIN signalling in neurodegeneration and neuroinflammation

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