Mitochondrial dysfunction in Parkinson’s disease

Hu, Qingsong; Wang, Guanghui

doi:10.1186/s40035-016-0060-6

Cited by 143 publications

(82 citation statements)

References 132 publications

(159 reference statements)

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“…Degeneration may begin in peripheral autonomic neurons and progress trans-neuronally in a retrograde manner to the brainstem and midbrain resulting in the loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) [138, 139]. The loss of dopaminergic (DA) neurons in the SNpc results in the motor symptoms seen with PD including rigidity, gait difficulty, resting tremors, bradykinesia, and dyskinesia [140].…”

Section: Involvement Of Neuronal Mitochondria In Acute Brain Injuriesmentioning

confidence: 99%

Adaptive responses of neuronal mitochondria to bioenergetic challenges: Roles in neuroplasticity and disease resistance

Raefsky

Mattson

2017

Free Radical Biology and Medicine

210

123

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An important concept in neurobiology is “neurons that fire together, wire together” which means that the formation and maintenance of synapses is promoted by activation of those synapses. Very similar to the effects of the stress of exercise on muscle cells, emerging findings suggest that neurons respond to activity by activating signaling pathways (e.g., Ca2+, CREB, PGC-1α, NF-κB) that stimulate mitochondrial biogenesis and cellular stress resistance. These pathways are also activated by aerobic exercise and food deprivation, two bioenergetic challenges of fundamental importance in the evolution of the brains of all mammals, including humans. The metabolic ‘switch’ in fuel source from liver glycogen store-derived glucose to adipose cell-derived fatty acids and their ketone metabolites during fasting and sustained exercise, appears to be a pivotal trigger of both brain-intrinsic and peripheral organ-derived signals that enhance learning and memory and underlying synaptic plasticity and neurogenesis. Brain-intrinsic extracellular signals include the excitatory neurotransmitter glutamate and the neurotrophic factor BDNF, and peripheral signals may include the liver-derived ketone 3-hydroxybutyrate and the muscle cell-derived protein irisin. Emerging findings suggest that fasting, exercise and an intellectually challenging lifestyle can protect neurons against the dysfunction and degeneration that they would otherwise suffer in acute brain injuries (stroke and head trauma) and neurodegenerative disorders including Alzheimer’s, Parkinson’s and Huntington’s disease. Among the prominent intracellular responses of neurons to these bioenergetic challenges are up-regulation of antioxidant defenses, autophagy/mitophagy and DNA repair. A better understanding of such fundamental hormesis-based adaptive neuronal response mechanisms is expected to result in the development and implementation of novel interventions to promote optimal brain function and healthy brain aging.

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Section: Involvement Of Neuronal Mitochondria In Acute Brain Injuriesmentioning

confidence: 99%

Adaptive responses of neuronal mitochondria to bioenergetic challenges: Roles in neuroplasticity and disease resistance

Raefsky

Mattson

2017

Free Radical Biology and Medicine

210

123

View full text Add to dashboard Cite

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“…However, little is known about the underlying function of mitophagy in ZnO NP-induced cell response in brain cells. 19,20 The PINK1/parkin pathway is widely recognized as one of the main molecular mechanisms that mediates the mitophagy process.…”

Section: Introductionmentioning

confidence: 99%

Involvement of PINK1/parkin-mediated mitophagy in ZnO nanoparticle-induced toxicity in BV-2 cells

Wei

Wang

Chen

et al. 2017

IJN

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With the increasing application of zinc oxide nanoparticles (ZnO NPs) in biological materials, the neurotoxicity caused by these particles has raised serious concerns. However, the underlying molecular mechanisms of the toxic effect of ZnO NPs on brain cells remain unclear. Mitochondrial damage has been reported to be a factor in the toxicity of ZnO NPs. PINK1/parkin-mediated mitophagy is a newly emerging additional function of autophagy that selectively degrades impaired mitochondria. Here, a PINK1 gene knockdown BV-2 cell model was established to determine whether PINK1/parkin-mediated mitophagy was involved in ZnO NP-induced toxicity in BV-2 cells. The expression of total parkin, mito-parkin, cyto-parkin, and PINK1 both in wild type and PINK1 −/− BV-2 cells was evaluated using Western blot analysis after the cells were exposed to 10 μg/mL of 50 nm ZnO NPs for 2, 4, 8, 12, and 24 h. The findings suggested that the downregulation of PINK1 resulted in a significant reduction in the survival rate after ZnO NP exposure compared with that of control cells. ZnO NPs were found to induce the transportation of parkin from the cytoplasm to the mitochondria, implying the involvement of mitophagy in ZnO NP-induced toxicity. The deletion of the PINK1 gene inhibited the recruitment of parkin to the mitochondria, causing failure of the cell to trigger mitophagy. The present study demonstrated that apart from autophagy, PINK1/parkin-mediated mitophagy plays a protective role in ZnO NP-induced cytotoxicity.

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“…Many genes associated with mitochondrial function are identified as causative genes of neurodegenerative diseases including Parkinson's disease, amyotrophic lateral sclerosis (ALS) , Charcot-Marie-Tooth (CMT) disease. For instance, VAMP-associated protein B and C (VAPB), Alsin and valosin-containing protein (VCP) are identified as ALS-causing genes; mitofusin 2 (MFN2) (Manfredi & Kawamata 2016), ganglioside-induced differentiationassociated protein 1 (GDAP1), dehydrogenase E1 and transketolase domain containing 1 (DHTKD1), mitochondrially encoded ATP synthase 6 (MT-ATP6), apoptosis-inducing factor, mitochondria associated 1 (AIFM1) and pyruvate dehydrogenase kinase 3 (PDK3) as CMT-causing genes; parkin RBR E3 ubiquitin protein ligase (PARK2), PTEN-induced putative kinase 1 (Pink1) and Parkinsonism-associated deglycase (DJ-1) as Parkinson's disease-causing gene (Hu & Wang 2016). Based on these facts, we consider that VMS and HS could possibly be caused by mitochondria functional disorder due to the defect in FAT4 function.…”

Section: Discussionmentioning

confidence: 99%

Neuron‐specific knockdown of the Drosophila fat induces reduction of life span, deficient locomotive ability, shortening of motoneuron terminal branches and defects in axonal targeting

et al. 2017

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Mutations in FAT4 gene, one of the human FAT family genes, have been identified in Van Maldergem syndrome (VMS) and Hennekam lymphangiectasia-lymphedema syndrome (HS). The FAT4 gene encodes a large protein with extracellular cadherin repeats, EGF-like domains and Laminin G-like domains. FAT4 plays a role in tumor suppression and planar cell polarity. Drosophila contains a human FAT4 homologue, fat. Drosophila fat has been mainly studied with Drosophila eye and wing systems. Here, we specially knocked down Drosophila fat in nerve system. Neuron-specific knockdown of fat shortened the life span and induced the defect in locomotive abilities of adult flies. In consistent with these phenotypes, defects in synapse structure at neuromuscular junction were observed in neuron-specific fat-knockdown flies. In addition, aberrations in axonal targeting of photoreceptor neuron in third-instar larvae were also observed, suggesting that fat involves in axonal targeting. Taken together, the results indicate that Drosophila fat plays an essential role in formation and/or maintenance of neuron. Both VMS and HS show mental retardation and neuronal defects. We therefore consider that these two rare human diseases could possibly be caused by the defect in FAT4 function in neuronal cells.

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Mitochondrial dysfunction in Parkinson’s disease

Cited by 143 publications

References 132 publications

Adaptive responses of neuronal mitochondria to bioenergetic challenges: Roles in neuroplasticity and disease resistance

Adaptive responses of neuronal mitochondria to bioenergetic challenges: Roles in neuroplasticity and disease resistance

Involvement of PINK1/parkin-mediated mitophagy in ZnO nanoparticle-induced toxicity in BV-2 cells

Neuron‐specific knockdown of the Drosophila fat induces reduction of life span, deficient locomotive ability, shortening of motoneuron terminal branches and defects in axonal targeting

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