Pathological structural conversion of α-synuclein at the mitochondria induces neuronal toxicity

Choi, Minee L.; Chappard, Alexandre; Singh, Bhanu; Maclachlan, Catherine; Rodrigues, Margarida; Fedotova, E. I.; Berezhnov, Alexey V.; Dey, Arghya; Peddie, Christopher J.; Athauda, Dilan; Virdi, Gurvir S.; Zhang, Weijia; Evans, James R.; Wernick, Anna I.; Zanjani, Zeinab Shadman; Angelova, Plamena R.; Esteras, Noemí; Vinokurov, Andrey Y.; Morris, Katie; Jeacock, Kiani; Tosatto, Laura; Little, Daniel; Gissen, Paul; Clarke, David J.; Kunath, Tilo; Collinson, Lucy; Klenerman, David; Abramov, Andrey Y.; Horrocks, Mathew H.; Gandhi, Sonia

doi:10.1038/s41593-022-01140-3

Cited by 107 publications

(94 citation statements)

References 72 publications

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“…However, this interaction accounts only partially for the α-SynOs’ neurotoxic effects [ 66 ]. The α-SynO oligomerization process is preferentially located on the membrane surface, and the mitochondrial membranes are more vulnerable to permeabilization [ 23 , 68 , 69 ]. This can be easily associated with the particular vulnerability of mitochondria in PD pathogenesis.…”

Section: Alpha-synuclein Oligomersmentioning

confidence: 99%

Alpha Synuclein: Neurodegeneration and Inflammation

Forloni

2023

IJMS

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Alpha-Synuclein (α-Syn) is one of the most important molecules involved in the pathogenesis of Parkinson’s disease and related disorders, synucleinopathies, but also in several other neurodegenerative disorders with a more elusive role. This review analyzes the activities of α-Syn, in different conformational states, monomeric, oligomeric and fibrils, in relation to neuronal dysfunction. The neuronal damage induced by α-Syn in various conformers will be analyzed in relation to its capacity to spread the intracellular aggregation seeds with a prion-like mechanism. In view of the prominent role of inflammation in virtually all neurodegenerative disorders, the activity of α-Syn will also be illustrated considering its influence on glial reactivity. We and others have described the interaction between general inflammation and cerebral dysfunctional activity of α-Syn. Differences in microglia and astrocyte activation have also been observed when in vivo the presence of α-Syn oligomers has been combined with a lasting peripheral inflammatory effect. The reactivity of microglia was amplified, while astrocytes were damaged by the double stimulus, opening new perspectives for the control of inflammation in synucleinopathies. Starting from our studies in experimental models, we extended the perspective to find useful pointers to orient future research and potential therapeutic strategies in neurodegenerative disorders.

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Section: Alpha-synuclein Oligomersmentioning

confidence: 99%

Alpha Synuclein: Neurodegeneration and Inflammation

Forloni

2023

IJMS

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“…The hiPSC derived from α-synuclein (A53T) PD patients shows sequestration of cardiolipin in aggregates of lipid-protein complexes. Further, these aggregates were shown to cause mitochondrial defects leading to neuronal cell death (Choi et al, 2022). Moreover, the oligomers and fibrillar forms of αsynuclein can independently generate ROS in occurrence of metal ions (Deas et al, 2016).…”

Section: Mutant Proteins Are Implicated In the Mitochondrial Damage O...mentioning

confidence: 99%

Disturb mitochondrial associated proteostasis: Neurodegeneration and imperfect ageing

Jagtap

Kumar

Kinger

et al. 2023

Front. Cell Dev. Biol.

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The disturbance in mitochondrial functions and homeostasis are the major features of neuron degenerative conditions, like Parkinson’s disease, Amyotrophic Lateral Sclerosis, and Alzheimer’s disease, along with protein misfolding. The aberrantly folded proteins are known to link with impaired mitochondrial pathways, further contributing to disease pathogenesis. Despite their central significance, the implications of mitochondrial homeostasis disruption on other organelles and cellular processes remain insufficiently explored. Here, we have reviewed the dysfunction in mitochondrial physiology, under neuron degenerating conditions. The disease misfolded proteins impact quality control mechanisms of mitochondria, such as fission, fusion, mitophagy, and proteasomal clearance, to the detriment of neuron. The adversely affected mitochondrial functional roles, like oxidative phosphorylation, calcium homeostasis, and biomolecule synthesis as well as its axes and contacts with endoplasmic reticulum and lysosomes are also discussed. Mitochondria sense and respond to multiple cytotoxic stress to make cell adapt and survive, though chronic dysfunction leads to cell death. Mitochondria and their proteins can be candidates for biomarkers and therapeutic targets. Investigation of internetworking between mitochondria and neurodegeneration proteins can enhance our holistic understanding of such conditions and help in designing more targeted therapies.

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“…Хотя заболевание традиционно связывается с нерастворимыми формами агрегированного α-синуклеина, именно растворимые промежуточные олигомеры характеризуются нейротоксичными эффектами. Было обнаружено, что олигомеры опосредуют аберрантный кальциевый сигналинг, перекисное окисление липидов, оксидативный стресс, митохондриальную дисфункцию и гибель нейронов [16][17][18]. В in vivo исследованиях было продемонстрировано, что формы α-синуклеина, склонные к образованию олигомеров и ингибирующие образование фибрилл, приводят к гибели дофаминергических нейронов.…”

Section: проверка на гомозиготность модификации в клоне 126-2-f4unclassified

Development of Murine Stem Cells With Conditional Knockout of Humanized Snca Gene

Patrakhanov

Pokrovsky

Karagodina

et al. 2023

Farm. farmakol. (Pâtigorsk)

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α-synuclein is one of the key molecular links in the pathogenesis of Parkinson’s disease. The accumulated data indicate that pathogenic mutations in the Snca gene are associated with the development of neurodegenerative brain damage, indicating the relevance of studying the synuclein neurobiological role.The aim of the study was to create a genetically modified clone of mouse stem cells with a conditional knockout of humanized α-synuclein, which can be used for the reinjection into mouse blastocysts, as well as for basic and applied in vitro research in the field of pathophysiology and neuropharmacology.Materials and methods. To create mouse stem cells with a conditional knockout of the humanized Snca gene, a previously obtained clone with the first Snca exon flanked by LoxP sites, was used. The CRISPR/Cas9-mediated homologous recombination system with donor DNA oligonucleotides of the human sites of the corresponding gene sites was used to humanize the fourth and fifth exons. Cas9 nuclease, single guide RNA, and donor DNA were transfected into mouse cells.Results. An approach to obtaining clones of mouse genetically modified stem cells expressing pathological humanized α-synuclein, has been proposed and implemented. The resulting clones were plated on Petri dishes for propagation and a further genetic analysis. Clone 126-2F4 was found out carrying the necessary genetic modifications. The results obtained are fundamentally important not only for understanding the development of the pathological process in α-synucleinopathies, but which is more important, for the development of new therapeutic approaches that will stop the extension of the human α-synuclein aggregation pathology throughout the nervous system, and the validation of these approaches in preclinical trials.Conclusion. As a result of the study, a strategy for CRISPR/Cas9-assisted homologous recombination in the genome of mouse embryonic stem cells has been developed to create a fully humanized Snca gene encoding α-synuclein, and the clone genome of mouse embryonic stem cells has been edited using a CRISPR technology. The RNA and DNA oligonucleotides necessary for the creation of RNP complexes that carry out a directed homologous recombination in the Snca locus of the mouse genome have been synthesized. The developed cell clone can serve to create a line of genetically modified mice that serve as a test system for pathophysiological and neuropharmacological studies associated with synucleinopathies. Herewith, before the induction of the Cre-dependent recombination, this line is a representative model for studying a biological role of mutant Snca. At the same time, after a Cre-dependent knockout activation, it is possible to imitate the pharmacological inhibition of α-synuclein, which is of particular interest for applied research in neuropharmacology.

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Pathological structural conversion of α-synuclein at the mitochondria induces neuronal toxicity

Cited by 107 publications

References 72 publications

Alpha Synuclein: Neurodegeneration and Inflammation

Alpha Synuclein: Neurodegeneration and Inflammation

Disturb mitochondrial associated proteostasis: Neurodegeneration and imperfect ageing

Development of Murine Stem Cells With Conditional Knockout of Humanized Snca Gene

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