Alpha-synuclein is a DNA binding protein that modulates DNA repair with implications for Lewy body disorders

Schaser, Allison J.; Osterberg, Valerie R.; Dent, Sydney E.; Stackhouse, Teresa L.; Wakeham, Colin M.; Boutros, Sydney Weber; Weston, Leah J.; Owen, Nichole; Weissman, Tamily A.; Luna, Esteban; Raber, Jacob; Luk, Kelvin C.; McCullough, Amanda K.; Woltjer, Randall L.; Unni, Vivek K.

doi:10.1038/s41598-019-47227-z

Cited by 207 publications

(225 citation statements)

References 79 publications

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“…Studies have reported that various structural forms of pathological state α‐syn, such as fibrils, fibers, oligomers, and amorphous oligomers, and their posttranslational modifications, such as phosphorylation, nitration, and ubiquitination, are neurotoxic (Chen & Feany, ; Cremades et al, ). There is a dynamic balance between normal and misfolded α‐syn under physiological conditions (Schaser et al, ). The balance is broken when cells are exposed to oxidative stress, poison, and other stress conditions.…”

Section: Discussionmentioning

confidence: 99%

Effect of Parkin on methamphetamine‐induced α‐synuclein degradation dysfunction in vitro and in vivo

et al. 2020

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Introduction Methamphetamine (METH) is a psychostimulant drug with complicated neurotoxicity, and abuse of METH is very common. Studies have shown that METH exposure causes alpha‐synuclein (α‐syn) accumulation. However, the mechanism of α‐syn accumulation has not been determined. Methods In this study, we established cell and animal models of METH intoxication to evaluate how METH affects α‐syn expression. In addition, to explore METH‐induced neurotoxicity, we measured the level of Parkin and the phosphorylation levels of α‐syn, Polo‐like kinase 2 (PLK2), the proteasome activity marker CD3δ, and the apoptosis‐related proteins Caspase‐3 and PARP. Parkin is a key enzyme in the ubiquitin–proteasome system. In addition, the effect of Parkin on METH‐induced neurotoxicity was investigated by overexpressing it in vitro and in vivo. Results METH exposure increased polyubiquitin and α‐syn expression, as did MG132. Furthermore, the level of Parkin and the interaction between Parkin and α‐syn decreased after METH exposure. Importantly, the increases in α‐syn expression and neurotoxicity were relieved by Parkin overexpression. Conclusions By establishing stable cell lines and animal models that overexpress Parkin, we confirmed Parkin as an important factor in METH‐induced α‐syn degradation dysfunction in vitro and in vivo. Parkin may be a promising target for the treatment of METH‐induced neurotoxicity.

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Section: Discussionmentioning

confidence: 99%

Effect of Parkin on methamphetamine‐induced α‐synuclein degradation dysfunction in vitro and in vivo

et al. 2020

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“…Finally, on H4 cells, it has been reported that the pS129α-syn form has an affinity for the nucleus, down-regulating important cell-cycle genes like CCNB1 and E2F8 (Pinho et al, 2019), indicating a plausible effect on progression between cellcycle phases. In addition, Schaser et al (2019) showed that pS129-α-syn is rapidly recruited to laser-induced DNA damage sites in the nucleus of in vivo mouse brain cells, as well as in a mouse primary cortical neuron system, having a plausible role on double-strand break repair (Schaser et al, 2019). This pathological form has also been observed within the nucleus of neurons in brain areas such as the basolateral amygdala, cortex, and hippocampus from aged p.A30P α-syn mice with impaired cognitive behavioral phenotypes.…”

Section: Nuclear Localization Of Alpha-synuclein Affects Transcriptiomentioning

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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“…Nonetheless, α-syn has been found to localize in and affect other cellular compartments aside synapses. In the nucleus, the protein physiologically interacts with and regulates histones (Goers et al, 2003;Kontopoulos et al, 2006;Schaser et al, 2019). On the other hand, its overexpression and phosphorylation modulates gene expression (Pinho et al, 2019), impairs the neuroprotective NF-κB signaling pathway (Yuan et al, 2008), and regulates the promoter of proliferator-activated receptor gamma coactivator 1 α (PGC1α), a transcription factor governing mitochondria biogenesis, to inhibit its transcription (Siddiqui et al, 2012).…”

Section: α-Synuclein: Physiological Function and Role In Pdmentioning

confidence: 99%

Nuclear Factor-κB Dysregulation and α-Synuclein Pathology: Critical Interplay in the Pathogenesis of Parkinson’s Disease

Bellucci

Bubacco

Longhena

et al. 2020

Front. Aging Neurosci.

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The loss of dopaminergic neurons of the nigrostriatal system underlies the onset of the typical motor symptoms of Parkinson's disease (PD). Lewy bodies (LB) and Lewy neurites (LN), proteinaceous inclusions mainly composed of insoluble α-synuclein (α-syn) fibrils are key neuropathological hallmarks of the brain of affected patients. Compelling evidence supports that in the early prodromal phases of PD, synaptic terminal and axonal alterations initiate and drive a retrograde degeneration process culminating with the loss of nigral dopaminergic neurons. This notwithstanding, the molecular triggers remain to be fully elucidated. Although it has been shown that α-syn fibrillary aggregation can induce early synaptic and axonal impairment and cause nigrostriatal degeneration, we still ignore how and why α-syn fibrillation begins. Nuclear factor-κB (NF-κB) transcription factors, key regulators of inflammation and apoptosis, are involved in the brain programming of systemic aging as well as in the pathogenesis of several neurodegenerative diseases. The NF-κB family of factors consists of five different subunits (c-Rel, p65/RelA, p50, RelB, and p52), which combine to form transcriptionally active dimers. Different findings point out a role of RelA in PD. Interestingly, the nuclear content of RelA is abnormally increased in nigral dopamine (DA) neurons and glial cells of PD patients. Inhibition of RelA exert neuroprotection against (1-methyl-4-phenyl-1,2,3,6tetrahydropyridine) MPTP and 1-methyl-4-phenylpyridinium (MPP+) toxicity, suggesting that this factor decreases neuronal resilience. Conversely, the c-Rel subunit can exert neuroprotective actions. We recently described that mice deficient for c-Rel develop a PD-like motor and non-motor phenotype characterized by progressive brain α-syn accumulation and early synaptic changes preceding the frank loss of nigrostriatal neurons. This evidence supports that dysregulations in this transcription factors may be involved in the onset of PD. This review highlights observations supporting a possible interplay between NF-κB dysregulation and α-syn pathology in PD, with the aim to disclose novel potential mechanisms involved in the pathogenesis of this disorder.

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Alpha-synuclein is a DNA binding protein that modulates DNA repair with implications for Lewy body disorders

Cited by 207 publications

References 79 publications

Effect of Parkin on methamphetamine‐induced α‐synuclein degradation dysfunction in vitro and in vivo

Effect of Parkin on methamphetamine‐induced α‐synuclein degradation dysfunction in vitro and in vivo

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

Nuclear Factor-κB Dysregulation and α-Synuclein Pathology: Critical Interplay in the Pathogenesis of Parkinson’s Disease

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