Alpha-synuclein-induced neurodegeneration is exacerbated in PINK1 knockout mice

Oliveras-Salvá, Marusela; Macchi, Francesca; Coessens, Valérie; Deleersnijder, Angélique; Gérard, Melanie; Perren, Anke Van der; Haute, Chris Van den; Baekelandt, Veerle

doi:10.1016/j.neurobiolaging.2014.04.032

Cited by 47 publications

(37 citation statements)

References 63 publications

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“…This defect seems attributable to the incorrect localization of mitochondria at the synapses which reduces the ATP provision. The increased evoked release that we here observe could be supported by the evidence that PINK1 knockout mice show an increased expression of alpha‐synuclein (Oliveras‐Salvá et al, ) which seems to be linked to an augmented assembly of SNARE‐complex thereby increase release probability (Burré et al, ).…”

Section: Discussionsupporting

confidence: 76%

Subtle alterations of excitatory transmission are linked to presynaptic changes in the hippocampus of PINK1‐deficient mice

Feligioni

Mango

Piccinin

et al. 2016

Synapse

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Homozygous or heterozygous mutations in the PTEN-induced kinase 1 (PINK1) gene have been linked to early-onset Parkinson's disease (PD). Several neurophysiological studies have demonstrated alterations in striatal synaptic plasticity along with impaired dopamine release in PINK1-deficient mice. Using electrophysiological methods, here we show that PINK1 loss of function causes a progressive increase of spontaneous glutamate-mediated synaptic events in the hippocampus, without influencing long-term potentiation. Moreover, fluorescence analysis reveals increased neurotrasmitter release although our biochemical results failed to detect which presynaptic proteins might be engaged. This study provides a novel role for PINK1 beyond the physiology of nigrostriatal dopaminergic circuit. Specifically, PINK1 might contribute to preserve synaptic function and glutamatergic homeostasis in the hippocampus, a brain region underlying cognition. The subtle changes in excitatory transmission here observed might be a pathogenic precursor to excitotoxic neurodegeneration and cognitive decline often observed in PD. Using electrophysiological and fluorescence techniques, we demonstrate that lack of PINK1 causes increased excitatory transmission and neurotransmitter release in the hippocampus, which might lead to the cognitive decline often observed in Parkinson's disease. Synapse 70:223-230,

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Section: Discussionsupporting

confidence: 76%

Subtle alterations of excitatory transmission are linked to presynaptic changes in the hippocampus of PINK1‐deficient mice

Feligioni

Mango

Piccinin

et al. 2016

Synapse

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“…In the rAAV-a-Syn models, the transgene expression is dependent on the serotype, the promoter, the injection site, and the titer of rAAV. The serotype rAAV2 is the most extensively used to date, probably because its production and purification methods are well-established (Van der Perren et al, 2014). However, there are some limitations associated with the rAAV2 serotype.…”

Section: Overexpression Of A-syn Mediated By Raavmentioning

confidence: 99%

Modeling Parkinson’s Disease With the Alpha-Synuclein Protein

et al. 2020

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Alpha-synuclein (a-Syn) is a key protein involved in Parkinson's disease (PD) pathology. PD is characterized by the loss of dopaminergic neuronal cells in the substantia nigra pars compacta and the abnormal accumulation and aggregation of a-Syn in the form of Lewy bodies and Lewy neurites. More precisely, the aggregation of a-Syn is associated with the dysfunctionality and degeneration of neurons in PD. Moreover, mutations in the SNCA gene, which encodes a-Syn, cause familial forms of PD and are the basis of sporadic PD risk. Given the role of the a-Syn protein in the pathology of PD, animal models that reflect the dopaminergic neuronal loss and the widespread and progressive formation of a-Syn aggregates in different areas of the brain constitute a valuable tool. Indeed, animal models of PD are important for understanding the molecular mechanisms of the disease and might contribute to the development and validation of new therapies. In the absence of animal models that faithfully reproduce human PD, in recent years, numerous animal models of PD based on a-Syn have been generated. In this review, we summarize the main features of the a-Syn pre-formed fibrils (PFFs) model and recombinant adenoassociated virus vector (rAAV) mediated a-Syn overexpression models, providing a detailed comparative analysis of both models. Here, we discuss how each model has contributed to our understanding of PD pathology and the advantages and weakness of each of them. Significance: Here, we show that injection of a-Syn PFFs and overexpression of a-Syn mediated by rAAV lead to a different pattern of PD pathology in rodents. First, a-Syn PFFs models trigger the Lewy body-like inclusions formation in brain regions directly interconnected with the injection site, suggesting that there is an inter-neuronal transmission of the a-Syn pathology. In contrast, rAAV-mediated a-Syn overexpression in the brain limits the a-Syn aggregates within the transduced neurons. Second, phosphorylated a-Syn inclusions obtained with rAAV are predominantly nuclear with a punctate appearance that becomes diffuse along the neuronal fibers, whereas a-Syn PFFs models lead to the formation of cytoplasmic aggregates of phosphorylated a-Syn reminiscent of Lewy bodies and Lewy neurites.

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“…When mitophagy fails to execute efficiently, the increased number of dysfunctional mitochondria in the cell can result in programmed (apoptotic) or nonprogrammed (necrotic) cell death, and degeneration into a diseased state [Mishra and Chan, 2014;Nikoletopoulou et al, 2015]. Since healthy mitochondria do not retain PINK1 on their outer membranes [Oliveras-Salv a et al, 2014;Steer et al, 2015], upregulating the PINK1/parkin mitophagic pathways should selectively remove dysfunctional mitochondria [Palikaras and Tavernarakis, 2014;Lionaki et al, 2015;Melser et al, 2015;Wei et al, 2015] thereby affording a new and actionable therapeutic target in the treatment of AD and PD [Narendra and Youle;Lazarou et al, 2012;Ashrafi et al, 2014;Hattori et al, 2014;McLelland et al, 2014;Tufi et al, 2014;Frake et al, 2015;Kazlauskaite and Muqit, 2015;Kroemer, 2015;Pickrell and Youle, 2015;Strappazzon et al, 2015].…”

Section: Apoptotic Priming In Mitochondriamentioning

confidence: 99%

Epigenetic Treatment of Neurodegenerative Disorders: Alzheimer and Parkinson Diseases

Irwin

Moos

Faller

et al. 2016

Drug Development Research

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Preclinical Research In this review, we discuss epigenetic-driven methods for treating neurodegenerative disorders associated with mitochondrial dysfunction, focusing on carnitinoid antioxidant-histone deacetylase inhibitors that show an ability to reinvigorate synaptic plasticity and protect against neuromotor decline in vivo. Aging remains a major risk factor in patients who progress to dementia, a clinical syndrome typified by decreased mental capacity, including impairments in memory, language skills, and executive function. Energy metabolism and mitochondrial dysfunction are viewed as determinants in the aging process that may afford therapeutic targets for a host of disease conditions, the brain being primary in such thinking. Mitochondrial dysfunction is a core feature in the pathophysiology of both Alzheimer and Parkinson diseases and rare mitochondrial diseases. The potential of new therapies in this area extends to glaucoma and other ophthalmic disorders, migraine, Creutzfeldt-Jakob disease, post-traumatic stress disorder, systemic exertion intolerance disease, and chemotherapy-induced cognitive impairment. An emerging and hopefully more promising approach to addressing these hard-to-treat diseases leverages their sensitivity to activation of master regulators of antioxidant and cytoprotective genes, antioxidant response elements, and mitophagy. Drug Dev Res 77 : 109-123, 2016. © 2016 Wiley Periodicals, Inc.

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Alpha-synuclein-induced neurodegeneration is exacerbated in PINK1 knockout mice

Cited by 47 publications

References 63 publications

Subtle alterations of excitatory transmission are linked to presynaptic changes in the hippocampus of PINK1‐deficient mice

Subtle alterations of excitatory transmission are linked to presynaptic changes in the hippocampus of PINK1‐deficient mice

Modeling Parkinson’s Disease With the Alpha-Synuclein Protein

Epigenetic Treatment of Neurodegenerative Disorders: Alzheimer and Parkinson Diseases

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