scholarly journals Cytosolic dsDNA of mitochondrial origin induces cytotoxicity and neurodegeneration in cellular and zebrafish models of Parkinson’s disease

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Hideaki Matsui ◽  
Junko Ito ◽  
Noriko Matsui ◽  
Tamayo Uechi ◽  
Osamu Onodera ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mitochondrial Dna ◽  
Cultured Cells ◽  
Cell Loss ◽  
Type I ◽  
Causative Role ◽  
Dnase Ii ◽  
Mitochondrial Origin

AbstractMitochondrial dysfunction and lysosomal dysfunction have been implicated in Parkinson’s disease (PD), but the links between these dysfunctions in PD pathogenesis are still largely unknown. Here we report that cytosolic dsDNA of mitochondrial origin escaping from lysosomal degradation was shown to induce cytotoxicity in cultured cells and PD phenotypes in vivo. The depletion of PINK1, GBA and/or ATP13A2 causes increases in cytosolic dsDNA of mitochondrial origin and induces type I interferon (IFN) responses and cell death in cultured cell lines. These phenotypes are rescued by the overexpression of DNase II, a lysosomal DNase that degrades discarded mitochondrial DNA, or the depletion of IFI16, which acts as a sensor for cytosolic dsDNA of mitochondrial origin. Reducing the abundance of cytosolic dsDNA by overexpressing human DNase II ameliorates movement disorders and dopaminergic cell loss in gba mutant PD model zebrafish. Furthermore, IFI16 and cytosolic dsDNA puncta of mitochondrial origin accumulate in the brain of patients with PD. These results support a common causative role for the cytosolic leakage of mitochondrial DNA in PD pathogenesis.

scholarly journals Neuroprotection in Parkinson’s disease: facts and hopes

2019 ◽  
Vol 127 (5) ◽  
pp. 821-829 ◽  
Author(s):  
András Salamon ◽  
Dénes Zádori ◽  
László Szpisjak ◽  
Péter Klivényi ◽  
László Vécsei
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cell Loss ◽  
Substantia Nigra Pars Compacta ◽  
Neuroprotective Agents ◽  
Dopaminergic Cell ◽  
Pathological Mechanism ◽  
Positive Results

AbstractParkinson’s disease (PD) is the second most common neurodegenerative disease worldwide. Behind the symptoms there is a complex pathological mechanism which leads to a dopaminergic cell loss in the substantia nigra pars compacta. Despite the strong efforts, curative treatment has not been found yet. To prevent a further cell death, numerous molecules were tested in terms of neuroprotection in preclinical (in vitro, in vivo) and in clinical studies as well. The aim of this review article is to summarize our knowledge about the extensively tested neuroprotective agents (Search period: 1991–2019). We detail the underlying pathological mechanism and summarize the most important results of the completed animal and clinical trials. Although many positive results have been reported in the literature, there is still no evidence that any of them should be used in clinical practice (Cochrane analysis was performed). Therefore, further studies are needed to better understand the pathomechanism of PD and to find the optimal neuroprotective agent(s).

scholarly journals Ablation of RIP3 protects from dopaminergic neurodegeneration in experimental Parkinson’s disease

2019 ◽  
Vol 10 (11) ◽  
Author(s):  
Pedro A. Dionísio ◽  
Sara R. Oliveira ◽  
Maria M. Gaspar ◽  
Maria J. Gama ◽  
Margarida Castro-Caldas ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cell Death ◽  
Cultured Cells ◽  
Substantia Nigra Pars Compacta ◽  
Neuronal Cultures ◽  
Interacting Protein ◽  
Dopaminergic Neurodegeneration

Abstract Parkinson’s disease (PD) is driven by dopaminergic neurodegeneration in the substantia nigra pars compacta (SN) and striatum. Although apoptosis is considered the main neurodegenerative mechanism, other cell death pathways may be involved. In this regard, necroptosis is a regulated form of cell death dependent on receptor interacting protein 3 (RIP3), a protein also implicated in apoptosis and inflammation independently of its pro-necroptotic activity. Here, we explored the role of RIP3 genetic deletion in in vivo and in vitro PD models. Firstly, wild-type (Wt) and RIP3 knockout (RIP3ko) mice were injected intraperitoneally with MPTP (40 mg/kg, i.p.), and sacrificed after either 6 or 30 days. RIP3ko protected from dopaminergic neurodegeneration in the SN of MPTP-injected mice, but this effect was independent of necroptosis. In keeping with this, necrostatin-1s (10 mg/kg/day, i.p.) did not afford full neuroprotection. Moreover, MPTP led to DNA fragmentation, caspase-3 activation, lipid peroxidation and BAX expression in Wt mice, in the absence of caspase-8 cleavage, suggesting intrinsic apoptosis. This was mimicked in primary cortical neuronal cultures exposed to the active MPTP metabolite. RIP3 deficiency in cultured cells and in mouse brain abrogated all phenotypes. Curiously, astrogliosis was increased in the striatum of MPTP-injected Wt mice and further exacerbated in RIP3ko mice. This was accompanied by absence of microgliosis and reposition of glial cell line-derived neurotrophic factor (GDNF) levels in the striata of MPTP-injected RIP3ko mice when compared to MPTP-injected Wt mice, which in turn showed a massive GDNF decrease. RIP3ko primary mixed glial cultures also presented decreased expression of inflammation-related genes upon inflammatory stimulation. These findings hint at possible undescribed non-necroptotic roles for RIP3 in inflammation and MPTP-driven cell death, which can contribute to PD progression.

scholarly journals SNCAE46K transgenic Drosophila Model of Parkinson’s Disease Confirmed the Causative Role of Oxidative Stress

2020 ◽  
Author(s):  
Samaneh Reiszadeh Jahromi ◽  
S R Ramesh ◽  
David I Finkelstein ◽  
Mohammad Haddadi
Keyword(s):  
Oxidative Stress ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Light And Electron Microscopy ◽  
Gene Mutations ◽  
Cell Loss ◽  
Genetic System ◽  
Causative Role ◽  
Microscopy Analysis ◽  
Transgenic Flies

AbstractParkinson’s disease (PD) is a class of neurodegenerative disorders in which, complex interactions of genetic and environmental agents are involved in the etiology of both sporadic and familial PD cases. α-synuclein-encoding SNCA gene is known as one of the major genetic contributors of this disease. E46K mutation in SNCA gene has not been investigated as intensive as other SNCA gene mutations including A30P and A53T. In this study, to induce PD in Drosophila flies, UAS-hSNCAWT and UAS-hSNCAE46K transgenic fly lines were constructed, where SNCA gene was over-expressed in flies brains using GAL4-UAS genetic system. Western blot analysis of head samples of SNCA-expressing flies verified SNCA expression at protein level. Light and electron microscopy analysis of ommatidial structures were performed to verify neurodegeneration as a result of α-synuclein gene overexpression in Drosophila transgenic flies. Confocal microscopy analysis of dopaminergic neuron clusters verified cell loss following SNCAE46K expression in the flies’ brain. E46K α-synuclein gene over-expression resulted in an evident decline in longevity as well as climbing ability of the flies. Biochemical studies of transgenic flies showed a remarkable decline in antioxidant enzymes activity and a significant increase in oxidative markers level as well as AchE enzyme activity. Oxidative stress has been known as a causal factor in PD pathogenesis, following expression of E46K mutant version of human SNCA gene. This Drosophila model is able to facilitate comparative studies of both molecular and cellular assays implicated in the assessment of neurotoxicity of different α-synuclein mutations.

scholarly journals The Parkinson's Disease-Related Protein DJ-1 Protects Dopaminergic Neurons in vivo and Cultured Cells from Alpha-Synuclein and 6-Hydroxydopamine Toxicity

2014 ◽  
Vol 15 (1) ◽  
pp. 13-23 ◽  
Author(s):  
Sara Batelli ◽  
Roberto William Invernizzi ◽  
Alessandro Negro ◽  
Eleonora Calcagno ◽  
Serena Rodilossi ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dopaminergic Neurons ◽  
Cultured Cells ◽  
Alpha Synuclein ◽  
Related Protein ◽  
6 Hydroxydopamine

scholarly journals Novel Approaches Used to Examine and Control Neurogenesis in Parkinson′s Disease

2021 ◽  
Vol 22 (17) ◽  
pp. 9608
Author(s):  
Alla B. Salmina ◽  
Marina R. Kapkaeva ◽  
Anna S. Vetchinova ◽  
Sergey N. Illarioshkin
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Rapid Development ◽  
Functional Integration ◽  
Cell Loss ◽  
Cell Replacement Therapy ◽  
And Control ◽  
The Brain

Neurogenesis is a key mechanism of brain development and plasticity, which is impaired in chronic neurodegeneration, including Parkinson’s disease. The accumulation of aberrant α-synuclein is one of the features of PD. Being secreted, this protein produces a prominent neurotoxic effect, alters synaptic plasticity, deregulates intercellular communication, and supports the development of neuroinflammation, thereby providing propagation of pathological events leading to the establishment of a PD-specific phenotype. Multidirectional and ambiguous effects of α-synuclein on adult neurogenesis suggest that impaired neurogenesis should be considered as a target for the prevention of cell loss and restoration of neurological functions. Thus, stimulation of endogenous neurogenesis or cell-replacement therapy with stem cell-derived differentiated neurons raises new hopes for the development of effective and safe technologies for treating PD neurodegeneration. Given the rapid development of optogenetics, it is not surprising that this method has already been repeatedly tested in manipulating neurogenesis in vivo and in vitro via targeting stem or progenitor cells. However, niche astrocytes could also serve as promising candidates for controlling neuronal differentiation and improving the functional integration of newly formed neurons within the brain tissue. In this review, we mainly focus on current approaches to assess neurogenesis and prospects in the application of optogenetic protocols to restore the neurogenesis in Parkinson’s disease.

In vivo multimodal (MRI, SPECT) imaging of the 6-OHDA rat model for Parkinson's disease correlated with behavior and histology

2005 ◽  
Vol 25 (1_suppl) ◽  
pp. S392-S392
Author(s):  
Nadja Van Camp ◽  
Koen Van Laere ◽  
Ruth Vreys ◽  
Marleen Verhoye ◽  
Erwin Lauwers ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Rat Model ◽  
Spect Imaging ◽  
Multimodal Mri

Pharmacological treatment with L-DOPA may reduce striatal dopamine transporter binding in in vivo imaging studies

2016 ◽  
Vol 55 (01) ◽  
pp. 21-28 ◽  
Author(s):  
C. Antke ◽  
H. Hautzel ◽  
H.-W. Mueller ◽  
S. Nikolaus
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Binding Sites ◽  
Human Subjects ◽  
Synaptic Cleft ◽  
Presynaptic Terminal ◽  
Imaging Studies ◽  
Psychiatric Conditions ◽  
Da Release

SummaryNumerous neurologic and psychiatric conditions are treated with pharmacological compounds, which lead to an increase of synaptic dopamine (DA) levels. One example is the DA precursor L-3,4-dihydroxyphenylalanine (L-DOPA), which is converted to DA in the presynaptic terminal. If the increase of DA concentrations in the synaptic cleft leads to competition with exogenous radioligands for presynaptic binding sites, this may have implications for DA transporter (DAT) imaging studies in patients under DAergic medication.This paper gives an overview on those findings, which, so far, have been obtained on DAT binding in human Parkinson’s disease after treatment with L-DOPA. Findings, moreover, are related to results obtained on rats, mice or non-human primates. Results indicate that DAT imaging may be reduced in the striata of healthy animals, in the unlesioned striata of animal models of unilateral Parkinson’s disease and in less severly impaired striata of Parkinsonian patients, if animal or human subjects are under acute or subchronic treatment with L-DOPA. If also striatal DAT binding is susceptible to alterations of synaptic DA levels, this may allow to quantify DA reuptake in analogy to DA release by assessing the competition between endogenous DA and the administered exogenous DAT radioligand.

Novel mitochondrial DNA mutations in Parkinson's disease

2002 ◽  
Vol 109 (5-6) ◽  
pp. 721-729 ◽  
Author(s):  
G. Richter ◽  
A. Sonnenschein ◽  
T. Grünewald ◽  
H. Reichmann ◽  
B. Janetzky
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mitochondrial Dna ◽  
Mitochondrial Dna Mutations ◽  
Dna Mutations

scholarly journals Growth Factor Therapy for Parkinson’s Disease: Alternative Delivery Systems

2021 ◽  
pp. 1-7
Author(s):  
Sarah Jarrin ◽  
Abrar Hakami ◽  
Ben Newland ◽  
Eilís Dowd
Keyword(s):  
Parkinson’S Disease ◽  
Gene Therapy ◽  
Parkinson's Disease ◽  
Growth Factors ◽  
Growth Factor ◽  
Ex Vivo ◽  
Brain Regions ◽  
Delivery Systems ◽  
Alternative Delivery

Despite decades of research and billions in global investment, there remains no preventative or curative treatment for any neurodegenerative condition, including Parkinson’s disease (PD). Arguably, the most promising approach for neuroprotection and neurorestoration in PD is using growth factors which can promote the growth and survival of degenerating neurons. However, although neurotrophin therapy may seem like the ideal approach for neurodegenerative disease, the use of growth factors as drugs presents major challenges because of their protein structure which creates serious hurdles related to accessing the brain and specific targeting of affected brain regions. To address these challenges, several different delivery systems have been developed, and two major approaches—direct infusion of the growth factor protein into the target brain region and in vivo gene therapy—have progressed to clinical trials in patients with PD. In addition to these clinically evaluated approaches, a range of other delivery methods are in various degrees of development, each with their own unique potential. This review will give a short overview of some of these alternative delivery systems, with a focus on ex vivo gene therapy and biomaterial-aided protein and gene delivery, and will provide some perspectives on their potential for clinical development and translation.

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