α-synucleinopathy exerts sex-dimorphic effects on the multipurpose DNA repair/redox protein APE1 in mice and humans

Miner, Kristin M.; Jamenis, Anuj S.; Bhatia, Tarun N.; Clark, Rachel N.; Rajasundaram, Dhivyaa; Sauvaigo, Sylvie; Mason, Daniel M.; Posimo, Jessica M.; Abraham, Nevil; DeMarco, Brett A.; Hu, Xiaoming; Stetler, R. Anne; Sanders, Laurie H.; Luk, Kelvin C.; Leak, Rehana K.

doi:10.1016/j.pneurobio.2022.102307

Cited by 9 publications

(11 citation statements)

References 180 publications

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“…Driven by damage specific glycosylases and the endonuclease activity of apurinic/apyrimidine endodeoxyribonuclease 1 (APEX1 /APE1), BER proceeds via short or long patch repair (Figure 7). Alterations to BER as a consequence of synucleiopathy have previously been reported, including an elevation of abasic sites [56] and key BER nucleases [2, 20, 45, 67]. Here, upregulation of principle BER nucleases APE1 and FLAP endonuclease 1 (FEN1) as well as other regulatory proteins, is consistent with the overactivation of long patch BER.…”

Section: Discussionsupporting

confidence: 75%

“…Alterations to BER as a consequence of synucleiopathy have previously been reported, including an elevation of abasic sites [56] and key BER nucleases [2, 20,45,67]. Here, upregulation of principle BER nucleases APE1 and FLAP endonuclease 1 (FEN1) as well as other regulatory proteins, is consistent with the overactivation of long patch BER.…”

Section: Base Excision Repairsupporting

confidence: 73%

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Post-mortem evidence for a reciprocal relationship between genomic DNA damage and alpha-synuclein pathology in dementia with Lewy bodies

Koss,

Todd,

Menon

et al. 2024

Preprint

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DNA damage and DNA damage repair (DDR) dysfunction are insults with broad implications on cellular physiology, including in proteostasis, and have been recently implicated in many neurodegenerative diseases. Alpha-synuclein (aSyn), a pre-synaptic and nuclear protein associated with neurodegenerative disorders known as synucleinopathies, has been implicated in DNA double strand break (DSB) repair function. Consistently, DSB induction has been demonstrated in cell and animal models of synucleinopathy. Nevertheless, the types of DNA damage and the contribution of DNA damage towards Lewy body (LB) formation in synucleinopathies are unknown. Here, we demonstrate the increase of DSB in neuronal and non-neuronal cellular populations of post-mortem temporal cortex tissue from dementia with Lewy body (DLB) patients and demonstrate increases in DSBs early at a presymptomatic age of aSyn transgenic mice. Strikingly, in postmortem DLB tissue, DNA damage-derived ectopic cytoplasmic genomic material (eCGM) was evident within the majority of LBs examined. The observed cellular pathology was consistent with nucleoproteasomal upregulation of associated DNA damage repair proteins, particularly in base excision repair and DSB repair pathways. Collectively our study demonstrates the early occurrence of DNA damage and associated nucleoproteasomal changes in response to nuclear aSyn pathology. Furthermore, the data suggests a potential involvement for DNA damage derived eCGM for the facilitation of cytoplasmic aSyn aggregates. Ultimately, uncovering pathological mechanisms underlying DNA damage in DLB sheds light into novel disease mechanisms and opens novel possibilities for diagnosing and treating synucleinopathies.

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Section: Discussionsupporting

confidence: 75%

Section: Base Excision Repairsupporting

confidence: 73%

Post-mortem evidence for a reciprocal relationship between genomic DNA damage and alpha-synuclein pathology in dementia with Lewy bodies

Koss,

Todd,

Menon

et al. 2024

Preprint

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“…ERCC1 mutant mice are also more sensitive to the neurotoxin MPTP [ 23 ]. Recently, Miner et al found that the loss of APE1 expression amplifies the formation of α-synuclein inclusions in vitro [ 51 ]. APE1 is a key enzyme in the base excision repair (BER) pathway, which mainly repairs oxidative DNA damage and the alkylation of bases [ 52 ].…”

Section: Evidence For Dna Damage-mediated Neurodegeneration In Pdmentioning

confidence: 99%

“…Therefore, a decrease in MRE11 may lead to DSBR defects [ 73 ]. In addition, the expression of the APE1 protein was reduced in the α-synuclein PFF mouse model compared to controls [ 51 ], and APE1 deficiency will result in the accumulation of oxidized DNA damage [ 74 ]. However, it is unclear whether the reduced levels of MRE11 or APE1 proteins directly contribute to the decreased efficiency of DSBR or BER in the PD model.…”

Section: Cause Of Dna Damage In Pdmentioning

confidence: 99%

DNA Damage-Mediated Neurotoxicity in Parkinson’s Disease

Wang

et al. 2023

IJMS

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Parkinson’s disease (PD) is the second most common neurodegenerative disease around the world; however, its pathogenesis remains unclear so far. Recent advances have shown that DNA damage and repair deficiency play an important role in the pathophysiology of PD. There is growing evidence suggesting that DNA damage is involved in the propagation of cellular damage in PD, leading to neuropathology under different conditions. Here, we reviewed the current work on DNA damage repair in PD. First, we outlined the evidence and causes of DNA damage in PD. Second, we described the potential pathways by which DNA damage mediates neurotoxicity in PD and discussed the precise mechanisms that drive these processes by DNA damage. In addition, we looked ahead to the potential interventions targeting DNA damage and repair. Finally, based on the current status of research, key problems that need to be addressed in future research were proposed.

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“…Previously, we found that PFF infusions targeted to the rear of the OB ( i.e. , centered in the bulbar AON) lead to limbic inclusions that are immunoreactive for phosphorylated α-synuclein (pSer129) and ubiquitin, and are stained with the Proteostat dye for amyloid protein aggregations ( Bhatia et al, 2021 ; Mason et al, 2016 ; Mason et al, 2019 ; Miner et al, 2022 ). Thus, we leveraged our mouse model to test the hypothesis that transient dietary exposure to PLX5622 would mitigate limbic α-synucleinopathy in aged mice of both sexes.…”

Section: Introductionmentioning

confidence: 99%

A 14-day pulse of PLX5622 modifies α-synucleinopathy in preformed fibril-infused aged mice of both sexes

Bhatia

Jamenis

Abbas

et al. 2023

Neurobiology of Disease

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α-synucleinopathy exerts sex-dimorphic effects on the multipurpose DNA repair/redox protein APE1 in mice and humans

Cited by 9 publications

References 180 publications

Post-mortem evidence for a reciprocal relationship between genomic DNA damage and alpha-synuclein pathology in dementia with Lewy bodies

Post-mortem evidence for a reciprocal relationship between genomic DNA damage and alpha-synuclein pathology in dementia with Lewy bodies

DNA Damage-Mediated Neurotoxicity in Parkinson’s Disease

A 14-day pulse of PLX5622 modifies α-synucleinopathy in preformed fibril-infused aged mice of both sexes

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