DNA damage preceding dopamine neuron degeneration in A53T human α-synuclein transgenic mice

Wang, Degui; Yu, Tianyu; Liu, Yongqiang; Yan, Jun; Guo, Yingli; Jing, Yu‐Hong; Yang, Xiaoyu; Song, Yanfeng; Tian, Yingxia

doi:10.1016/j.bbrc.2016.11.008

Cited by 19 publications

(15 citation statements)

References 15 publications

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“…The evidence for the presence of extensive genome damage in PD-affected human brains and various PD model systems [29–31] led us to examine DNA breaks in α-Syn-overexpressing cells in presence of pro-oxidant Fe or Cu salts. Fe has been shown to accumulate in α-Syn-rich Lewy bodies in the PD brain and within α-Syn-rich inclusions in PD neuronal cells [6, 46].…”

Section: Resultsmentioning

confidence: 99%

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Chromatin-Bound Oxidized α-Synuclein Causes Strand Breaks in Neuronal Genomes in in vitro Models of Parkinson’s Disease

Vasquez

Mitra

Hegde

et al. 2017

JAD

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Alpha-synuclein (α-Syn) overexpression and misfolding/aggregation in degenerating dopaminergic neurons have long been implicated in Parkinson’s disease (PD). The neurotoxicity of α-Syn is enhanced by iron (Fe) and other pro-oxidant metals, leading to generation of reactive oxygen species in PD brain. Although α-Syn is predominantly localized in presynaptic nerve terminals, a small fraction exists in neuronal nuclei. However, the functional and/or pathological role of nuclear α-Syn is unclear. Following up on our earlier report that α-Syn directly binds DNA in vitro, here we confirm the nuclear localization and chromatin association of α-Syn in neurons using proximity ligation and chromatin immunoprecipitation analysis. Moderate (~2-fold) increase in α-Syn expression in neural lineage progenitor cells (NPC) derived from induced pluripotent human stem cells (iPSCs) or differentiated SHSY-5Y cells caused DNA strand breaks in the nuclear genome, which was further enhanced synergistically by Fe salts. Furthermore, α-Syn required nuclear localization for inducing genome damage as revealed by the effect of nucleus versus cytosol-specific mutants. Enhanced DNA damage by oxidized and misfolded/oligomeric α-Syn suggests that DNA nicking activity is mediated by the chemical nuclease activity of an oxidized peptide segment in the misfolded α-Syn. Consistent with this finding, a marked increase in Fe-dependent DNA breaks was observed in NPCs from a PD patient-derived iPSC line harboring triplication of the SNCA gene. Finally, α-Syn combined with Fe significantly promoted neuronal cell death. Together, these findings provide a novel molecular insight into the direct role of α-Syn in inducing neuronal genome damage, which could possibly contribute to neurodegeneration in PD.

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Section: Resultsmentioning

confidence: 99%

“…Interestingly, the level of DNA damage accumulation in PD-affected brain regions seems to broadly correlate with disease severity, which is linked to α-Syn pathology and metal accumulation/oxidative stress [29–31]. However, a direct link between α-Syn toxicity and genome damage has not been investigated.…”

Section: Introductionmentioning

confidence: 99%

Chromatin-Bound Oxidized α-Synuclein Causes Strand Breaks in Neuronal Genomes in in vitro Models of Parkinson’s Disease

Vasquez

Mitra

Hegde

et al. 2017

JAD

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“…Age-related increases in DNA damage, as well as energy deficits and oxidative stress, have been observed in dopaminergic neurons following exposure to specific environmental and genetic factors [ 231 ]. DNA damage has been detected at symptom onset in animal models of PD [ 232 ], implying it may contribute to disease progression. DNA damage and associated death of dopamine neurons are also present in brain tissues from PD patients [ 233 ].…”

Section: Mechanisms Of Cell Death Induced By Dna Damage In Neurodegen...mentioning

confidence: 99%

The Complex Mechanisms by Which Neurons Die Following DNA Damage in Neurodegenerative Diseases

Shadfar

Brocardo

Atkin

2022

IJMS

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Human cells are exposed to numerous exogenous and endogenous insults every day. Unlike other molecules, DNA cannot be replaced by resynthesis, hence damage to DNA can have major consequences for the cell. The DNA damage response contains overlapping signalling networks that repair DNA and hence maintain genomic integrity, and aberrant DNA damage responses are increasingly described in neurodegenerative diseases. Furthermore, DNA repair declines during aging, which is the biggest risk factor for these conditions. If unrepaired, the accumulation of DNA damage results in death to eliminate cells with defective genomes. This is particularly important for postmitotic neurons because they have a limited capacity to proliferate, thus they must be maintained for life. Neuronal death is thus an important process in neurodegenerative disorders. In addition, the inability of neurons to divide renders them susceptible to senescence or re-entry to the cell cycle. The field of cell death has expanded significantly in recent years, and many new mechanisms have been described in various cell types, including neurons. Several of these mechanisms are linked to DNA damage. In this review, we provide an overview of the cell death pathways induced by DNA damage that are relevant to neurons and discuss the possible involvement of these mechanisms in neurodegenerative conditions.

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“…αSyn monomers are mainly located at presynaptic vesicles whereas misfolded αSyn oligomers and high molecular weight aggregates can be found throughout the entire neuron. αSyn pathology affects diverse cellular functions, including: increasing reactive oxygen species (ROS), impairing mitochondrial function [1,2], reducing proteasomal degradation and autophagy [3,4] as well as inducing DNA damage [5]. However, the pathogenesis of PD does not follow a lineair succession of events and is rather charactersiezed by self-enhancing mechanisms.…”

Section: Introductionmentioning

confidence: 99%

Rab7 Reduces α-Synuclein Toxicity in Rats and Primary Neurons

Szegő

Haute

Höfs

et al. 2021

Preprint

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BackgroundDuring the pathogenesis of Parkinson’s disease (PD), aggregation of alpha-synuclein (αSyn) induces a vicious cycle of cellular impairments that lead to neurodegeneration. Consequently, removing toxic αSyn aggregates constitutes a plausible strategy against PD. In this work, we tested whether stimulating the autolysosomal degradation of αSyn aggregates through the Ras-related in brain 7 (Rab7) pathway can reverse αSyn-induced cellular impairment and prevent neurodegeneration in vivo.MethodsThe disease-related A53T mutant of αSyn was expressed in primary neurons and in dopaminergic neurons of the rat brain simultaneously with wild type (WT) Rab7 or its dominant-negative T22N mutant as a control. The cellular integrity was quantified by morphological and biochemical analyses.ResultsIn primary neurons, WT Rab7 rescued the αSyn -induced loss of neurons and neurites. Furthermore, Rab7 decreased the amount of reactive oxygen species and the amount of Triton X-100 insoluble αSyn. In rat brain, WT Rab7 reduced αSyn -induced loss of dopaminergic axon terminals in the striatum and the loss of dopaminergic dendrites in the substantia nigra pars reticulata. Further, WT Rab7 lowered αSyn pathology as quantified by phosphorylated αSyn staining. Finally, WT Rab7 attenuated αSyn-induced DNA damage in primary neurons and rat brain.ConclusionRab7 reduced αSyn-induced pathology, ameliorated αSyn-induced neuronal degeneration, oxidative stress and DNA damage. These findings indicate that Rab7 is able to disrupt the vicious cycle of cellular impairment, αSyn pathology and neurodegeneration present in PD. Stimulation of Rab7 and the autolysosomal degradation pathway could therefore constitute a beneficial strategy for PD.

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DNA damage preceding dopamine neuron degeneration in A53T human α-synuclein transgenic mice

Cited by 19 publications

References 15 publications

Chromatin-Bound Oxidized α-Synuclein Causes Strand Breaks in Neuronal Genomes in in vitro Models of Parkinson’s Disease

Chromatin-Bound Oxidized α-Synuclein Causes Strand Breaks in Neuronal Genomes in in vitro Models of Parkinson’s Disease

The Complex Mechanisms by Which Neurons Die Following DNA Damage in Neurodegenerative Diseases

Rab7 Reduces α-Synuclein Toxicity in Rats and Primary Neurons

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