Alpha-synuclein fragments trigger distinct aggregation pathways

Chakroun, Tasnim; Evsyukov, Valentin; Nykänen, Niko-Petteri; Höllerhage, Matthias; Schmidt, Andreas; Kamp, Frits; Ruf, Viktoria; Wurst, Wolfgang; Rösler, Thomas W.; Höglinger, Günter U.

doi:10.1038/s41419-020-2285-7

Cited by 30 publications

(31 citation statements)

References 56 publications

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“…Silencing of the two most upregulated genes CCND1 and CCND2 , involved in the G0/G1 cell cycle initiation, revealed that siRNA against CCND1 alone and in combination with CCND2 markedly reduced cytotoxicity levels. Taken together, early-stage intracellular accumulation of αSyn in human mesencephalic post-mitotic neurons ( Chakroun et al, 2020 ) is accompanied by an altered expression of miRNAs, leading to an enrichment of G0/G1 cell cycle genes. Among them, CCND1 seems to be functionally involved in αSyn-mediated cell death, as shown by siRNA-mediated intervention.…”

Section: Discussionmentioning

confidence: 99%

“…Adenoviral SNCA overexpression results in increased intracellular αSyn protein levels and ∼ 50% cytotoxicity levels at day 6 post transduction in differentiated LUHMES neurons ( Höllerhage et al, 2014 ; Chakroun et al, 2020 ). In the present study, we performed a miRNome-wide screen in SNCA -overexpressing LUHMES neurons at day 4 post transduction and focused on (1) altered levels of miRNAs and their target genes and (2) identifying a functional involvement of dysregulated biological pathways.…”

Section: Introductionmentioning

confidence: 99%

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Comprehensive miRNome-Wide Profiling in a Neuronal Cell Model of Synucleinopathy Implies Involvement of Cell Cycle Genes

Findeiss

Schwarz

Evsyukov

et al. 2021

Front. Cell Dev. Biol.

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Growing evidence suggests that epigenetic mechanisms like microRNA-mediated transcriptional regulation contribute to the pathogenesis of parkinsonism. In order to study the influence of microRNAs (miRNAs), we analyzed the miRNome 2 days prior to major cell death in α-synuclein-overexpressing Lund human mesencephalic neurons, a well-established cell model of Parkinson’s disease (PD), by next-generation sequencing. The expression levels of 23 miRNAs were significantly altered in α-synuclein-overexpressing cells, 11 were down- and 12 upregulated (P < 0.01; non-adjusted). The in silico analysis of known target genes of these miRNAs was complemented by the inclusion of a transcriptome dataset (BeadChip) of the same cellular system, revealing the G0/G1 cell cycle transition to be markedly enriched. Out of 124 KEGG-annotated cell cycle genes, 15 were present in the miRNA target gene dataset and six G0/G1 cell cycle genes were found to be significantly altered upon α-synuclein overexpression, with five genes up- (CCND1, CCND2, and CDK4 at P < 0.01; E2F3, MYC at P < 0.05) and one gene downregulated (CDKN1C at P < 0.001). Additionally, several of these altered genes are targeted by miRNAs hsa-miR-34a-5p and hsa-miR-34c-5p, which also modulate α-synuclein expression levels. Functional intervention by siRNA-mediated knockdown of the cell cycle gene cyclin D1 (CCND1) confirmed that silencing of cell cycle initiation is able to substantially reduce α-synuclein-mediated cytotoxicity. The present findings suggest that α-synuclein accumulation induces microRNA-mediated aberrant cell cycle activation in post-mitotic dopaminergic neurons. Thus, the mitotic cell cycle pathway at the level of miRNAs might offer interesting novel therapeutic targets for PD.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Comprehensive miRNome-Wide Profiling in a Neuronal Cell Model of Synucleinopathy Implies Involvement of Cell Cycle Genes

Findeiss

Schwarz

Evsyukov

et al. 2021

Front. Cell Dev. Biol.

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“…Recently, the relevance of aSyn fragments in the extracellular space was shown not only for spreading but also for aggregation and the formation of different strains. These fragments are also able to mediate the aggregation of endogenous full-length aSyn [ 155 ].…”

Section: Lewy Pathology: More Than Simply One Mechanism or Hypothementioning

confidence: 99%

Alpha-Synuclein: Mechanisms of Release and Pathology Progression in Synucleinopathies

Brás

Outeiro

2021

Cells

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The accumulation of misfolded alpha-synuclein (aSyn) throughout the brain, as Lewy pathology, is a phenomenon central to Parkinson’s disease (PD) pathogenesis. The stereotypical distribution and evolution of the pathology during disease is often attributed to the cell-to-cell transmission of aSyn between interconnected brain regions. The spreading of conformationally distinct aSyn protein assemblies, commonly referred as strains, is thought to result in a variety of clinically and pathologically heterogenous diseases known as synucleinopathies. Although tremendous progress has been made in the field, the mechanisms involved in the transfer of these assemblies between interconnected neural networks and their role in driving PD progression are still unclear. Here, we present an update of the relevant discoveries supporting or challenging the prion-like spreading hypothesis. We also discuss the importance of aSyn strains in pathology progression and the various putative molecular mechanisms involved in cell-to-cell protein release. Understanding the pathways underlying aSyn propagation will contribute to determining the etiology of PD and related synucleinopathies but also assist in the development of new therapeutic strategies.

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“…The role of α-syn misfolding in the initiation of PD is well established (Mahul-Mellier et al, 2020). Several studies report on targeting α-syn aggregation and synthesis as a potential therapeutic option in PD (Fields et al, 2019;Chakroun et al, 2020;Gabr and Peccati, 2020;Mahul-Mellier et al, 2020;Ryan et al, 2020). Here, it is important to mention that native α-syn plays a crucial role in releasing the neurotransmitter associated with SV due to its greater curvature, but its over-expression is reported to inhibit the release of neurotransmitters (Sulzer and Edwards, 2019;Cai et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

“Janus-Faced” α-Synuclein: Role in Parkinson’s Disease

Ray

Mahalakshmi

Tuladhar

et al. 2021

Front. Cell Dev. Biol.

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Parkinson’s disease (PD) is a pathological condition characterized by the aggregation and the resultant presence of intraneuronal inclusions termed Lewy bodies (LBs) and Lewy neurites which are mainly composed of fibrillar α-synuclein (α-syn) protein. Pathogenic aggregation of α-syn is identified as the major cause of LBs deposition. Several mutations in α-syn showing varied aggregation kinetics in comparison to the wild type (WT) α-syn are reported in PD (A30P, E46K, H 50Q, G51D, A53E, and A53T). Also, the cell-to-cell spread of pathological α-syn plays a significant role in PD development. Interestingly, it has also been suggested that the pathology of PD may begin in the gastrointestinal tract and spread via the vagus nerve (VN) to brain proposing the gut–brain axis of α-syn pathology in PD. Despite multiple efforts, the behavior and functions of this protein in normal and pathological states (specifically in PD) is far from understood. Furthermore, the etiological factors responsible for triggering aggregation of this protein remain elusive. This review is an attempt to collate and present latest information on α-syn in relation to its structure, biochemistry and biophysics of aggregation in PD. Current advances in therapeutic efforts toward clearing the pathogenic α-syn via autophagy/lysosomal flux are also reviewed and reported.

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Alpha-synuclein fragments trigger distinct aggregation pathways

Cited by 30 publications

References 56 publications

Comprehensive miRNome-Wide Profiling in a Neuronal Cell Model of Synucleinopathy Implies Involvement of Cell Cycle Genes

Comprehensive miRNome-Wide Profiling in a Neuronal Cell Model of Synucleinopathy Implies Involvement of Cell Cycle Genes

Alpha-Synuclein: Mechanisms of Release and Pathology Progression in Synucleinopathies

“Janus-Faced” α-Synuclein: Role in Parkinson’s Disease

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