α-Synuclein is a Novel Microtubule Dynamase

Cartelli, Daniele; Aliverti, Alessandro; Barbiroli, Alberto; Santambrogio, Carlo; Ragg, Enzio; Casagrande, Francesca; Cantele, Francesca; Beltramone, Silvia; Marangon, Jacopo; Gregorio, Carmelita De; Pandini, V.; Emanuele, Marco; Chieregatti, Evelina; Pieraccini, Stefano; Holmqvist, Staffan; Bubacco, Luigi; Roybon, Laurent; Pezzoli, Gianni; Grandori, Rita; Arnal, Isabelle; Cappelletti, Graziella

doi:10.1038/srep33289

Cited by 86 publications

(94 citation statements)

References 55 publications

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“…The staining of pSer129 + inclusions with the Proteostat aggresomal dye is consistent with previous studies on similarities between Lewy bodies and aggresomes (112,161). The formation of the aggresome is microtubule-dependent (96) and α-synuclein appears to interact with tubulin, perhaps serving as a microtubule dynamase (6,37,135). Aggresomes are hypothesized to serve as a protective mechanism facilitating cellular survival under proteotoxic conditions (162), as they are observed in 53%-60% of nonapoptotic cells but only 10%-13% of apoptotic cells in vitro (161).…”

Section: α-Synucleinopathic Inclusions In the Preformed Fibril Model supporting

confidence: 89%

The center of olfactory bulb‐seeded α‐synucleinopathy is the limbic system and the ensuing pathology is higher in male than in female mice

et al. 2019

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At early disease stages, Lewy body disorders are characterized by limbic vs. brainstem α‐synucleinopathy, but most preclinical studies have focused solely on the nigrostriatal pathway. Furthermore, male gender and advanced age are two major risk factors for this family of conditions, but their influence on the topographical extents of α‐synucleinopathy and the degree of cell loss are uncertain. To fill these gaps, we infused α‐synuclein fibrils in the olfactory bulb/anterior olfactory nucleus complex—one of the earliest and most frequently affected brain regions in Lewy body disorders—in 3‐month‐old female and male mice and in 11‐month‐old male mice. After 6 months, we observed that α‐synucleinopathy did not expand significantly beyond the limbic connectome in the 9‐month‐old male and female mice or in the 17‐month‐old male mice. However, the 9‐month‐old male mice had developed greater α‐synucleinopathy, smell impairment and cell loss than age‐matched females. By 10.5 months post‐infusion, fibril treatment hastened mortality in the 21.5‐month‐old males, but the inclusions remained centered in the limbic system in the survivors. Although fibril infusions reduced the number of cells expressing tyrosine hydroxylase in the substantia nigra of young males at 6 months post‐infusion, this was not attributable to true cell death. Furthermore, mesencephalic α‐synucleinopathy, if present, was centered in mesolimbic circuits (ventral tegmental area/accumbens) rather than within strict boundaries of the nigral pars compacta, which were defined here by tyrosine hydroxylase immunolabel. Nonprimate models cannot be expected to faithfully recapitulate human Lewy body disorders, but our murine model seems reasonably suited to (i) capture some aspects of Stage IIb of Lewy body disorders, which displays a heavier limbic than brainstem component compared to incipient Parkinson’s disease; and (ii) leverage sex differences and the acceleration of mortality following induction of olfactory α‐synucleinopathy.

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Section: α-Synucleinopathic Inclusions In the Preformed Fibril Model supporting

confidence: 89%

The center of olfactory bulb‐seeded α‐synucleinopathy is the limbic system and the ensuing pathology is higher in male than in female mice

et al. 2019

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“…In the present study, we observed enhanced miR-17-5p expression and concomitant reduction of its target Map6 in the colonic MP of psA30P mice, suggesting that miR-17-5p-mediated regulation of Map6 could be involved in the initiation of PD pathogenesis. Interestingly, α-synuclein interacts with microtubules in HeLa cells 89 and preferably with tyrosinated tubulin in human mesencephalic neurons 90 . In agreement with our in vitro results, A30P α-synucleins regulate the microtubule network in PD.…”

Section: Discussionmentioning

confidence: 99%

Functional and molecular early enteric biomarkers for Parkinson’s disease in mice and men

Gries

Christmann

Schulte

et al. 2020

Preprint

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Parkinson's disease (PD) usually has a late clinical onset. The lack of early biomarkers for the disease represents a major challenge for developing timely treatment interventions. Here, we use an -synuclein-overexpressing transgenic (Th-1-SNCA-A30P) mouse model of PD to identify appropriate candidate markers in the gut for early stages of PD before hallmark symptoms begin to manifest. A30P mice did not show alterations in gait parameters at 2 months of age, and these mice were therefore defined as pre-symptomatic A30P mice (psA30P). We discovered early functional motility changes in the gut and early molecular dysregulations in the myenteric plexus of psA30P mice by comparative protein and miRNA profiling and cell culture experiments. We found that the proteins neurofilament light chain, vesicle-associated membrane protein 2 and calbindin 2, together with the miRNAs that regulate them, are potential biomarkers of early PD that may facilitate timely treatment and/or prevention of PD in men.

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“…In particular, the identification of familial cases with multiplications of SNCA (the gene encoding for α‐syn) revealed a strong correlation between α‐syn accumulation and aggregation, and disease severity . Although the physiological role of α‐syn is not fully characterized, it has been shown that it plays important roles in the supply of synaptic vesicles in presynaptic terminals and in the movement of microtubules …”

Section: Mutations In Genes Encoding Autophagic‐lysosomal Proteins Inmentioning

confidence: 99%

“…[23][24][25] Although the physiological role of α-syn is not fully characterized, it has been shown that it plays important roles in the supply of synaptic vesicles in presynaptic terminals 26,27 and in the movement of microtubules. 28,29 VPS35 encodes vacuolar protein sorting-associated protein 35, which is involved in the endosomal-lysosomal trafficking associated to autophagy. Mutations on VPS35 cause a rare form of autosomal-dominant PD.…”

Section: Mutations In Genes Encoding Autophagic-lysosomal Proteinsmentioning

confidence: 99%

The Vicious Cycle Between α‐Synuclein Aggregation and Autophagic‐Lysosomal Dysfunction

et al. 2019

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The accumulation and misfolding of α‐synuclein (α‐syn) represent the main pathological hallmark of PD. Overexpression of α‐syn and failure of cellular protein degradation systems play a major role in α‐syn aggregation. The discovery of PD‐associated genes related to the autophagic‐lysosomal pathway, such as VPS35, LRRK2, GBA1, SMPD1, GALC, ASAH1, SCARB2, CTSD, CTSB, and GLA, confirms the involvement of cellular clearance systems dysfunction in PD pathogenesis. Of importance, lysosomal enzyme activity is altered both in genetic and sporadic PD. Decreased lysosomal enzymes activities were measured in the same brain regions where α‐syn accumulates, suggesting that a crosstalk between α‐syn aggregation and autophagic‐lysosomal impairment may exist. The understanding of autophagic‐lysosomal pathway dysfunctions’ role in the pathogenesis and progression of synucleinopathies opened new perspectives for novel possible therapeutic strategies. In this article, the evidences and mechanisms of the reciprocal relation between autophagic‐lysosomal pathway impairment and misfolded α‐syn aggregation and propagation are reviewed, together with the most promising compounds targeting autophagic‐lysosomal pathway restoration as a disease‐modifying strategy for PD treatment. © 2019 International Parkinson and Movement Disorder Society

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α-Synuclein is a Novel Microtubule Dynamase

Cited by 86 publications

References 55 publications

The center of olfactory bulb‐seeded α‐synucleinopathy is the limbic system and the ensuing pathology is higher in male than in female mice

The center of olfactory bulb‐seeded α‐synucleinopathy is the limbic system and the ensuing pathology is higher in male than in female mice

Functional and molecular early enteric biomarkers for Parkinson’s disease in mice and men

The Vicious Cycle Between α‐Synuclein Aggregation and Autophagic‐Lysosomal Dysfunction

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