Alpha-synuclein prevents the formation of spherical mitochondria and apoptosis under oxidative stress

Menges, Stefanie; Minakaki, Georgia; Schaefer, Patrick; Meixner, H; Prots, Iryna; Schlötzer‐Schrehardt, Ursula; Friedland, Kristina; Winner, Beate; Outeiro, Tiago F.; Winklhofer, Konstanze F.; Arnim, Christine A. F. Von; Xiang, Wei; Winkler, Jürgen; Klucken, Jochen

doi:10.1038/srep42942

Cited by 69 publications

(52 citation statements)

References 98 publications

(142 reference statements)

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“…is linked to neurodegenerative diseases (Chen and Chan, 2010). A recent study found that the overexpression of α-syn in neurons can confer protection against ROS, since it decreases a type of dynamin-related protein 1 (Drp1)dependent mitochondrial fragmentation related to H 2 O 2 and 6-hydroxydopamine, known as mitosphere (hyperpolarized mitochondria with a spherical form), which precedes the activation of apoptosis mediated by Caspase 3 (Menges et al, 2017). However, further research is needed in order to know the α-syn baseline concentration contribution in mesencephalic dopaminergic neurons, in order to understand the importance of α-syn in the most affected cell type, which indeed has a high rate of ROS.…”

Section: Alpha-synuclein Is Associated With Mitochondrial Morphologicmentioning

confidence: 99%

Alpha-Synuclein Physiology and Pathology: A Perspective on Cellular Structures and Organelles

et al. 2020

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Alpha-synuclein (α-syn) is localized in cellular organelles of most neurons, but many of its physiological functions are only partially understood. α-syn accumulation is associated with Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy as well as other synucleinopathies; however, the exact pathomechanisms that underlie these neurodegenerative diseases remain elusive. In this review, we describe what is known about α-syn function and pathophysiological changes in different cellular structures and organelles, including what is known about its behavior as a prionlike protein. We summarize current knowledge of α-syn and its pathological forms, covering its effect on each organelle, including aggregation and toxicity in different model systems, with special interest on the mitochondria due to its relevance during the apoptotic process of dopaminergic neurons. Moreover, we explore the effect that α-syn exerts by interacting with chromatin remodeling proteins that add or remove histone marks, up-regulate its own expression, and resume the impairment that α-syn induces in vesicular traffic by interacting with the endoplasmic reticulum. We then recapitulate the events that lead to Golgi apparatus fragmentation, caused by the presence of α-syn. Finally, we report the recent findings about the accumulation of α-syn, indirectly produced by the endolysosomal system. In conclusion, many important steps into the understanding of α-syn have been made using in vivo and in vitro models; however, the time is right to start integrating observational studies with mechanistic models of α-syn interactions, in order to look at a more complete picture of the pathophysiological processes underlying α-synucleinopathies.

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Section: Alpha-synuclein Is Associated With Mitochondrial Morphologicmentioning

confidence: 99%

Alpha-Synuclein Physiology and Pathology: A Perspective on Cellular Structures and Organelles

et al. 2020

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“…It has also been suggested that αS might be involved in the maintenance of pools of SVs at the synapses (Cooper et al, 2006;Wislet-Gendebien et al, 2006;Auluck et al, 2010;Nemani et al, 2010;Vargas et al, 2014), a role that is associated with its ability to mediate interactions between SVs (Gitler et al, 2008;Soper et al, 2008;Diao et al, 2013;Fusco et al, 2016b). A common characteristics of the majority of the putative functions so far proposed for αS -including SV trafficking (Wislet-Gendebien et al, 2006;Gitler et al, 2008;Soper et al, 2008;Auluck et al, 2010;Burre et al, 2010Burre et al, , 2014Diao et al, 2013), ER-to-Golgi vesicle trafficking (Cooper et al, 2006;Gitler et al, 2008), mitochondrial binding (Zigoneanu et al, 2012;Maltsev et al, 2013;Menges et al, 2017) -involves the binding with biological membranes (Zigoneanu et al, 2012;Maltsev et al, 2013;Snead and Eliezer, 2014). Indeed, the partition between membrane bound and unbound states of αS appears to be highly regulated in vivo (Lee et al, 2002) and influences its aggregation propensity (Perrin et al, 2001;Necula et al, 2003;Sharon et al, 2003;Zhu and Fink, 2003;Auluck et al, 2010;Comellas et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

A Role of Cholesterol in Modulating the Binding of α-Synuclein to Synaptic-Like Vesicles

et al. 2020

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α-Synuclein (αS) is a presynaptic protein whose aggregation is associated with Parkinson's disease (PD). Although the physiological function of αS is still unclear, several lines of evidence indicate that this protein may play a role in the trafficking of synaptic vesicles (SVs) during neurotransmitter release, a task associated with its ability to bind SVs and promote their clustering. It is therefore crucial to identify the cellular factors that modulate this process. To address this question, using nuclear magnetic resonance (NMR) spectroscopy we have characterized the role of cholesterol, a major component of the membrane of SVs, in the binding of αS with synaptic-like vesicles.Our results indicate that cholesterol can act as a modulator of the overall affinity of αS for SVs by reducing the local affinity of the region spanning residues 65-97 in the non-amyloid-β component (NAC) of the protein. The increased population of bound states that expose the region 65-97 to the solvent was found to induce stronger vesiclevesicle interactions by αS. These results provide evidence that cholesterol modulates the clustering of synaptic vesicles induced by (α)S, and supports the role of the disorder-toorder equilibrium of the NAC region in the modulation of the biological properties of the membrane-bound state of αS.

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“…31,40 The higher membrane potential measured in mutant cells exposed to H 2 O 2 might mirror an increased tendency to form hyperpolarized mitochondrial fragments, which has been described at moderate levels of oxidative stress. 42 These hypotheses will be the subject of further research. We therefore assume that the amino acid changes p.Arg217His and p.Arg217Cys entail a gain of pathological function that interferes with the physiological SLC25A24 function regulating the mPTP.…”

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confidence: 96%

De Novo Mutations in SLC25A24 Cause a Craniosynostosis Syndrome with Hypertrichosis, Progeroid Appearance, and Mitochondrial Dysfunction

Ehmke

Graul‐Neumann

Smorag

et al. 2017

The American Journal of Human Genetics

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Gorlin-Chaudhry-Moss syndrome (GCMS) is a dysmorphic syndrome characterized by coronal craniosynostosis and severe midface hypoplasia, body and facial hypertrichosis, microphthalmia, short stature, and short distal phalanges. Variable lipoatrophy and cutis laxa are the basis for a progeroid appearance. Using exome and genome sequencing, we identified the recurrent de novo mutations c.650G>A (p.Arg217His) and c.649C>T (p.Arg217Cys) in SLC25A24 in five unrelated girls diagnosed with GCMS. Two of the girls had pronounced neonatal progeroid features and were initially diagnosed with Wiedemann-Rautenstrauch syndrome. SLC25A24 encodes a mitochondrial inner membrane ATP-Mg/P carrier. In fibroblasts from affected individuals, the mutated SLC25A24 showed normal stability. In contrast to control cells, the probands' cells showed mitochondrial swelling, which was exacerbated upon treatment with hydrogen peroxide (HO). The same effect was observed after overexpression of the mutant cDNA. Under normal culture conditions, the mitochondrial membrane potential of the probands' fibroblasts was intact, whereas ATP content in the mitochondrial matrix was lower than that in control cells. However, upon HO exposure, the membrane potential was significantly elevated in cells harboring the mutated SLC25A24. No reduction of mitochondrial DNA copy number was observed. These findings demonstrate that mitochondrial dysfunction with increased sensitivity to oxidative stress is due to the SLC25A24 mutations. Our results suggest that the SLC25A24 mutations induce a gain of pathological function and link mitochondrial ATP-Mg/P transport to the development of skeletal and connective tissue.

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Alpha-synuclein prevents the formation of spherical mitochondria and apoptosis under oxidative stress

Cited by 69 publications

References 98 publications

Alpha-Synuclein Physiology and Pathology: A Perspective on Cellular Structures and Organelles

Alpha-Synuclein Physiology and Pathology: A Perspective on Cellular Structures and Organelles

A Role of Cholesterol in Modulating the Binding of α-Synuclein to Synaptic-Like Vesicles

De Novo Mutations in SLC25A24 Cause a Craniosynostosis Syndrome with Hypertrichosis, Progeroid Appearance, and Mitochondrial Dysfunction

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