Synapsin III deficiency hampers α-synuclein aggregation, striatal synaptic damage and nigral cell loss in an AAV-based mouse model of Parkinson’s disease

Faustini, Gaia; Longhena, Francesca; Varanita, Tatiana; Bubacco, Luigi; Pizzi, Marina; Missale, Cristina; Benfenati, Fabio; Björklund, Anders; Spano, Pier Franco; Bellucci, Arianna

doi:10.1007/s00401-018-1892-1

Cited by 58 publications

(69 citation statements)

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“…[6] Moreover, we showed that Syn III is another key component of aSyn insoluble fibrils extracted from the post-mortem brains of sporadic PD patients [7] and that Syn III is a crucial mediator of aSyn aggregation and toxicity. [8] Strikingly, our most recent findings suggest that threo-methylphenidate (MPH), a monoamine re-uptake inhibitor clinically approved for the treatment of attention deficits and hyperactivity disorder (ADHD) [9] and for ameliorating gait freezing in advanced PD, [10][11][12][13][14] is able to stimulate an aSyn/Syn III-mediated locomotor response, specifically in aSyn transgenic mice at a pathological stage that exhibit severe dopaminergic functional deficits. [15] This MPH action is lost upon in vivo Syn III gene silencing, [15] thus suggesting that this protein may act as a target for MPH.…”

Section: Introductionmentioning

confidence: 99%

Design and Synthesis of Fluorescent Methylphenidate Analogues for a FRET‐Based Assay of Synapsin III Binding

et al. 2020

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We previously described synapsin III (Syn III) as a synaptic phosphoprotein that controls dopamine release in cooperation with α‐synuclein (aSyn). Moreover, we found that in Parkinson's disease (PD), Syn III also participates in aSyn aggregation and toxicity. Our recent observations point to threo‐methylphenidate (MPH), a monoamine re‐uptake inhibitor that efficiently counteracts the freezing‐gait characteristic of advanced PD, as a ligand for Syn III. We have designed and synthesised two different fluorescently labelled MPH derivatives, one with Rhodamine Red (RHOD) and one with 5‐carboxytetramethylrhodamine (TAMRA), to be used for assessing MPH binding to Syn III by FRET. TAMRA‐MPH exhibited the ideal characteristics to be used as a FRET acceptor, as it was able to enter into the SK‐N‐SH cells and could interact specifically with human green fluorescent protein (GFP)‐tagged Syn III but not with GFP alone. Moreover, the uptake of TAMRA‐MPH and co‐localization with Syn III was also observed in primary mesencephalic neurons. These findings support that MPH is a Syn III ligand and that TAMRA‐conjugated drug molecules might be valuable tools to study drug‐ligand interactions by FRET or to detect Syn III in cytological and histological samples.

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Section: Introductionmentioning

confidence: 99%

Design and Synthesis of Fluorescent Methylphenidate Analogues for a FRET‐Based Assay of Synapsin III Binding

et al. 2020

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“…In terms of pathophysiology and implications, the results obtained in the longitudinal section indicates that at early stages in PD, the serotonergic system seems to be affected showing a disconnection of Raphe nuclei from projecting regions in the graph analyses. Axonal degenerations and loss of synaptic proteins and efficiency might account for the "disconnection" detected in this study at all 3 levels (brainstem/subcortical/cortical regions) [48,49].…”

Section: Discussionmentioning

confidence: 73%

High-resolution PET imaging reveals subtle impairment of the serotonin transporter in an early non-depressed Parkinson’s disease cohort

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Ferreira

Svenningsson

et al. 2020

Eur J Nucl Med Mol Imaging

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Purpose The serotonin transporter (SERT) is a biochemical marker for monoaminergic signaling in brain and has been suggested to be involved inthe pathophysiology of Parkinson's disease (PD). The aim of this PET study was to examine SERT availability in relevant brain regions in early stages ofnon-depressed PD patients. Methods In a cross-sectional study, 18 PD patients (13 M/5F, 64 ± 7 years, range 46-74 years, disease duration 2.9 ± 2.6 years; UPDRS motor 21.9 ± 5.2) and 20 age-and gender-matched healthy control (HC) subjects (15 M/5F, 61 ± 7 years, range 50-72 years) were included. In a subsequent longitudinal phase, ten of the PD patients (7 M/3F, UPDRS motor 20.6 ± 6.9) underwent a second PET measurement after 18-24 months. After a 3-T MRI acquisition, baseline PET measurements were performed with [ 11 C]MADAM using a high-resolution research tomograph. The non-displaceablebinding potential (BP ND) was chosen as the outcome measure and was estimated at voxel level on wavelet-aided parametric images, by using the Logan graphical analysis and the cerebellum as reference region. A molecular template was generated to visualize and define different subdivisions of the raphe nuclei in the brainstem. Subortical and cortical regions of interest were segmented using FreeSurfer. Univariate analyses and multivariate network analyses were performed on the PET data. Results The univariate region-based analysis showed no differences in SERT levels when the PD patients were compared with the HC neither at baseline or after 2 years of follow-up. The multivariate network analysis also showed no differences at baseline. However, prominent changes in integration and segregation measures were observed at follow-up, indicating a disconnection of the cortical and subcortical regions from the three nuclei of the raphe. Conclusion We conclude that the serotoninergic system in PD patients seems to become involved with a network dysregulation as the disease progresses, suggesting a disturbed serotonergic signaling from raphe nuclei to target subcortical and cortical regions.

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“…In PINK1 knock out mice, overexpression of a-Syn in the substantia nigra resulted in enhanced dopaminergic degeneration as well as high levels of phosphorylated a-Syn, suggesting that the loss of PINK1 leads to an increased sensitivity to a-Syn-induced neuropathology (Oliveras-Salvá et al, 2014). The injection of rAAV-mediating human a-Syn overexpression in knock out mice for synapsin III (Syn III) shows that silencing of Syn III could prevent the a-Syn aggregation (Faustini et al, 2018). Moreover, the genetic background of animals is important in response to a-Syn overexpression.…”

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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Synapsin III deficiency hampers α-synuclein aggregation, striatal synaptic damage and nigral cell loss in an AAV-based mouse model of Parkinson’s disease

Cited by 58 publications

References 57 publications

Design and Synthesis of Fluorescent Methylphenidate Analogues for a FRET‐Based Assay of Synapsin III Binding

Design and Synthesis of Fluorescent Methylphenidate Analogues for a FRET‐Based Assay of Synapsin III Binding

High-resolution PET imaging reveals subtle impairment of the serotonin transporter in an early non-depressed Parkinson’s disease cohort

Modeling Parkinson’s Disease With the Alpha-Synuclein Protein

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