Comparison between α-synuclein wild-type and A53T mutation in a progressive Parkinson's disease model

Lu, Jianqing; Sun, Fenyong; Ma, Hong; Qing, Hong; Deng, Yulin

doi:10.1016/j.bbrc.2015.07.007

Cited by 20 publications

(17 citation statements)

References 18 publications

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“…Overexpression of wild type a-Syn or PD-associated mutants (A53T or A30P a-Syn) utilizing rAAV leads to a progressive loss of dopaminergic neurons in the SNc, a loss of dopamine terminals in the striatum (Koprich et al, 2010;Koprich et al, 2011;Oliveras-Salvá et al, 2013;Bourdenx et al, 2015;Caudal et al, 2015;Lu et al, 2015;Ip et al, 2017), and a reduction of striatal dopamine content (Koprich et al, 2011;Ip et al, 2017). However, the extent of neurodegeneration achieved with the rAAV model is variable among the different studies.…”

Section: Overexpression Of A-syn Mediated By Raavmentioning

confidence: 99%

“…Unlike models based on the administration of a-Syn PFFs, in these models, the a-Synimmunoreactive structures are commonly nuclear with a small and punctate appearance. Some studies have demonstrated that these structures are proteinase-K resistant (Koprich et al, 2010;Taschenberger et al, 2012;Lu et al, 2015;Ip et al, 2017) or urearesistant (Oliveras-Salvá et al, 2013), but they do not reproduce the morphological features of human Lewy bodies. Our group have found that the overexpression of E46K human a-Syn mediated by rAAV2/9 in the striatum leads to the accumulation of multiple pa-Syn-immunoreactive structures in striatal cells, most likely in medium spiny projection neurons because we observe a diffuse staining of pa-Syn in the terminals in the projection fields (the globus pallidus and substantia nigra reticulata) at 12 weeks after rAAV injection (Figure 3).…”

Section: Overexpression Of A-syn Mediated By Raavmentioning

confidence: 99%

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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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Section: Overexpression Of A-syn Mediated By Raavmentioning

confidence: 99%

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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“…Neural progenitor cell lines from PD patient with α-synuclein overexpression exhibited a reduced ability to differentiate into DA neurons (Oliveira et al, 2015). Moreover, overexpression of wild-type or A53T mutated α-synuclein by recombinant adeno-associated virus mediated-overexpression in the rat substantia nigra (SN) induced the loss of DA neurons and the formation of α-synuclein aggregation (Lu et al, 2015). Interestingly, Parkin deficiency facilitated the cell-to-cell transmission of α-synuclein (Cha et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Elevated Hapln2 Expression Contributes to Protein Aggregation and Neurodegeneration in an Animal Model of Parkinson's Disease

Wang

Zhou

Zhang

et al. 2016

Front. Aging Neurosci.

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Parkinson's disease (PD), the second most common age-associated progressive neurodegenerative disorder, is characterized by the loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SN). The pathogenesis of PD and the mechanisms underlying the degeneration of DA neurons are still not fully understood. Our previous quantitative proteomics study revealed that hyaluronan and proteoglycan binding link protein 2 (Hapln2) is one of differentially expressed proteins in the substantia nigra tissues from PD patients and healthy control subjects. However, the potential role of Hapln2 in PD pathogenesis remains elusive. In the present study, we characterized the expression pattern of Hapln2. In situ hybridization revealed that Hapln2 mRNA was widely expressed in adult rat brain with high abundance in the substantia nigra. Immunoblotting showed that expression levels of Hapln2 were markedly upregulated in the substantia nigra of either human subjects with Parkinson's disease compared with healthy control. Likewise, there were profound increases in Hapln2 expression in neurotoxin 6-hydroxydopamine-treated rat. Overexpression of Hapln2 in vitro increased vulnerability of MES23.5 cells, a dopaminergic cell line, to 6-hydroxydopamine. Moreover, Hapln2 overexpression led to the formation of cytoplasmic aggregates which were co-localized with ubiquitin and E3 ligases including Parkin, Gp78, and Hrd1 in vitro. Endogenous α-synuclein was also localized in Hapln2-containing aggregates and ablation of Hapln2 led to a marked decrease of α-synuclein in insoluble fraction compared with control. Thus, Hapln2 is identified as a novel factor contributing to neurodegeneration in PD. Our data provides new insights into the cellular mechanism underlying the pathogenesis in PD.

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“…Its expression level was positively correlated with the severity of PD [87]. Accumulating evidences proved that the abnormal deposit of α-syn could result in neurotoxicity through a gain-of-function manner [88][89][90]. The research carried out by Recasens et al [91] showed that the nigrostriatal neurons in mice and monkeys appeared to degenerate slowly after injection of Lewy bodies extracted from patients with PD.…”

Section: α-Synuclein Aggregation and Parkinson Diseasementioning

confidence: 99%

“…Multiple lines of proofs have shown that α-syn can be transformed from its normal structure into an unusual disease-associated structure influenced by many factors containing inhesion factors and external factors [6,7,88,93,94]. On the one hand, within α-syn itself, some of its mutations can induce a more toxic effect on DA neurons and were more vulnerable to aggregation [88,95,96]. For example, A53T mutant-type α-syn protein had the higher propensity to aggregate compared with the wild-type α-syn protein, as a result of the increased β-sheet formation and lack of strong intramolecular long-range interactions in the N-terminal region [96].…”

Section: α-Synuclein Aggregation and Parkinson Diseasementioning

confidence: 99%