Rotenone aggravates PD-like pathology in A53T mutant human α-synuclein transgenic mice in an age-dependent manner

Cao, Jia-Xin; Chen, Haichao; Du, Hongwu; Xi, Xiao-Xia; Sun, Jing; Yin, Jie; Jing, Yu‐Hong; Gao, Liping

doi:10.3389/fnagi.2022.842380

Cited by 3 publications

(4 citation statements)

References 53 publications

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“…PD is usually detected in the later stages when neurons have degenerated ( Lotankar et al, 2017 ). The important feature of neural degeneration is the deletion of DA neurons in substantia nigra pars compacta ( Chen et al, 2022 ), which is accompanied by nervous system malfunction ( Antunes et al, 2021 ). In our study, MPTP treatment could induce DA neuronal loss and nervous system injury in zebrafish, validating the applicability of MPTP for generating PD model as previously reported ( Ren et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

The alleviative effect of Calendula officinalis L. extract against Parkinson’s disease-like pathology in zebrafish via the involvement of autophagy activation

Wang

Ping

et al. 2023

Front. Neurosci.

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IntroductionParkinson’s disease (PD) is the second most prevalent neurodegenerative disorder. However, effective preventative or therapeutic agents for PD remain largely limited. Marigold Calendula officinalis L. (CoL) has been reported to possess a wide range of biological activities, but its neuroprotective activity including anti-neurodegenerative diseases is unclear. Here, we aim to investigate whether the extract of CoL (ECoL) has therapeutic activity on PD.MethodsWe identified the chemical composition of flavonoid, an important active ingredient in ECoL, by a targeted HPLC-Q-TOF-MS analysis. Subsequently, we evaluated the anti-PD effect of ECoL by using zebrafish PD model induced by 1-methyl-4-phenyl-1-1,2,3,6-tetrahydropyridine (MPTP). After ECoL+MPTP co-treatments, the changes of dopaminergic neurons, neural vasculature, nervous system, and locomotor activity were examined, respectively. The expressions of genes related to neurodevelopment and autophagy were detected by RT-qPCR. Further, the interaction between autophagy regulators and ECoL flavonoids was predicted using molecular docking method.ResultsAs a result, 5 kinds of flavonoid were identified in ECoL, consisting of 121 flavones and flavonols, 32 flavanones, 22 isoflavonoids, 11 chalcones and dihydrochalcones, and 17 anthocyanins. ECoL significantly ameliorated the loss of dopaminergic neurons and neural vasculature, restored the injury of nervous system, and remarkably reversed the abnormal expressions of neurodevelopment-related genes. Besides, ECoL notably inhibited the locomotor impairment in MPTP-induced PD-like zebrafish. The underlying anti-PD effect of ECoL may be implicated in activating autophagy, as ECoL significantly upregulated the expressions of genes related to autophagy, which contributes to the degradation of α-synuclein aggregation and dysfunctional mitochondria. Molecular docking simulation showed the stable interaction between autophagy regulators (Pink, Ulk2, Atg7, and Lc3b) and 10 main compounds of flavonoid in ECoL, further affirming the involvement of autophagy activation by ECoL in anti-PD action.ConclusionOur results suggested that ECoL has the anti-PD effect, and ECoL might be a promising therapeutic candidate for PD treatment.

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Section: Discussionmentioning

confidence: 99%

The alleviative effect of Calendula officinalis L. extract against Parkinson’s disease-like pathology in zebrafish via the involvement of autophagy activation

Wang

Ping

et al. 2023

Front. Neurosci.

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“…44 Low-dose oral rotenone (3-10 mg/kg) has been widely used by various teams to replicate gut first PD. 39,40,[43][44][45]47,48,50 The primary phenotypes of this model include SNpc neurodegeneration, motor deficits, and decreased gut motility. This phenotype is observed in young and old mice using both high (30 mg/kg) or low (3-10 mg/kg)dose regimens, suggesting that age is not a crucial factor (Table 1).…”

Section: Key Pointsmentioning

confidence: 99%

“…"Multi-hit" models use a combination of pathogenic factors. In addition to combining genetic overexpression of α-synuclein with gut delivery of environmental toxins 50,51 or PFFs, 90,94,97 gut inflammation can be used to accelerate parkinsonian pathology. [112][113][114][115] Pathogenesis in these models may not always involve ascending pathology and may require systemic inflammation 113 ; however, peripheral mechanisms are likely involved.…”

Section: Additional and Emerging Rodent Models Of Gut-first Pdmentioning

confidence: 99%

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Experimental models of gut‐first Parkinson's disease: A systematic review

Videlock

Xing

Yehya

et al. 2023

Neurogastroenterology Motil

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Background There is strong support from studies in humans and in animal models that Parkinson's disease (PD) may begin in the gut. This brings about a unique opportunity for researchers in the field of neurogastroenterology to contribute to advancing the field and making contributions that could lead to the ability to diagnose and treat PD in the premotor stages. Lack of familiarity with some of the aspects of the experimental approaches used in these studies may present a barrier for neurogastroenterology researchers to enter the field. Much remains to be understood about intestinal‐specific components of gut‐first PD pathogenesis and the field would benefit from contributions of enteric and central nervous system neuroscientists. Purpose To address these issues, we have conducted a systematic review of the two most frequently used experimental models of gut‐first PD: transneuronal propagation of α‐synuclein preformed fibrils and oral exposure to environmental toxins. We have reviewed the details of these studies and present methodological considerations for the use of these models. Our aim is that this review will serve as a framework and useful reference for neuroscientists, gastroenterologists, and neurologists interested in applying their expertise to advancing our understanding of gut‐first PD.

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Lewy bodies, iron, inflammation and neuromelanin: pathological aspects underlying Parkinson’s disease

Riederer

Nagatsu

Youdim³

et al. 2023

J Neural Transm

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Since the description of some peculiar symptoms by James Parkinson in 1817, attempts have been made to define its cause or at least to enlighten the pathology of “Parkinson’s disease (PD).” The vast majority of PD subtypes and most cases of sporadic PD share Lewy bodies (LBs) as a characteristic pathological hallmark. However, the processes underlying LBs generation and its causal triggers are still unknown. ɑ-Synuclein (ɑ-syn, encoded by the SNCA gene) is a major component of LBs, and SNCA missense mutations or duplications/triplications are causal for rare hereditary forms of PD. Thus, it is imperative to study ɑ-syn protein and its pathology, including oligomerization, fibril formation, aggregation, and spreading mechanisms. Furthermore, there are synergistic effects in the underlying pathogenic mechanisms of PD, and multiple factors—contributing with different ratios—appear to be causal pathological triggers and progression factors. For example, oxidative stress, reduced antioxidative capacity, mitochondrial dysfunction, and proteasomal disturbances have each been suggested to be causal for ɑ-syn fibril formation and aggregation and to contribute to neuroinflammation and neural cell death. Aging is also a major risk factor for PD. Iron, as well as neuromelanin (NM), show age-dependent increases, and iron is significantly increased in the Parkinsonian substantia nigra (SN). Iron-induced pathological mechanisms include changes of the molecular structure of ɑ-syn. However, more recent PD research demonstrates that (i) LBs are detected not only in dopaminergic neurons and glia but in various neurotransmitter systems, (ii) sympathetic nerve fibres degenerate first, and (iii) at least in “brain-first” cases dopaminergic deficiency is evident before pathology induced by iron and NM. These recent findings support that the ɑ-syn/LBs pathology as well as iron- and NM-induced pathology in “brain-first” cases are important facts of PD pathology and via their interaction potentiate the disease process in the SN. As such, multifactorial toxic processes posted on a personal genetic risk are assumed to be causal for the neurodegenerative processes underlying PD. Differences in ratios of multiple factors and their spatiotemporal development, and the fact that common triggers of PD are hard to identify, imply the existence of several phenotypical subtypes, which is supported by arguments from both the “bottom-up/dual-hit” and “brain-first” models. Therapeutic strategies are necessary to avoid single initiation triggers leading to PD.

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Rotenone aggravates PD-like pathology in A53T mutant human α-synuclein transgenic mice in an age-dependent manner

Cited by 3 publications

References 53 publications

The alleviative effect of Calendula officinalis L. extract against Parkinson’s disease-like pathology in zebrafish via the involvement of autophagy activation

The alleviative effect of Calendula officinalis L. extract against Parkinson’s disease-like pathology in zebrafish via the involvement of autophagy activation

Experimental models of gut‐first Parkinson's disease: A systematic review

Lewy bodies, iron, inflammation and neuromelanin: pathological aspects underlying Parkinson’s disease

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