Retrotransposon activation by distressed mitochondria in neurons

Baeken, Marius W.; Moosmann, Bernd; Hajieva, Parvana

doi:10.1016/j.bbrc.2020.02.106

Cited by 22 publications

(29 citation statements)

References 29 publications

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“…First, the uncoupler FCCP induces mitochondrial stress without immediately increasing ROS formation. Second, we applied the antioxidant phenothiazine (PHT), an established, selective radical scavenger in PD models [ 18 – 20 ]. Finally, a PHT control group was monitored.…”

Section: Resultsmentioning

confidence: 99%

The selective degradation of sirtuins via macroautophagy in the MPP+ model of Parkinson’s disease is promoted by conserved oxidation sites

et al. 2021

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The sirtuin (SIRT) protein family has been of major research interest over the last decades because of their involvement in aging, cancer, and cell death. SIRTs have been implicated in gene and metabolic regulation through their capacity to remove acyl groups from lysine residues in proteins in an NAD+-dependent manner, which may alter individual protein properties as well as the histone–DNA interaction. Since SIRTs regulate a wide range of different signaling cascades, a fine-tuned homeostasis of these proteins is imperative to guarantee the function and survival of the cell. So far, however, how exactly this homeostasis is established has remained unknown. Here, we provide evidence that neuronal SIRT degradation in Parkinson’s disease (PD) models is executed by autophagy rather than the proteasome. In neuronal Lund human mesencephalic (LUHMES) cells, all seven SIRTs were substrates for autophagy and showed an accelerated autophagy-dependent degradation upon 1-methyl-4-phenylpyridinium (MPP+) mediated oxidative insults in vitro, whereas the proteasome did not contribute to the removal of oxidized SIRTs. Through blockade of endogenous H2O2 generation and supplementation with the selective radical scavenger phenothiazine (PHT), we could identify H2O2-derived species as the responsible SIRT-oxidizing agents. Analysis of all human SIRTs suggested a conserved regulatory motif based on cysteine oxidation, which may have triggered their degradation via autophagy. High amounts of H2O2, however, rapidly carbonylated selectively SIRT2, SIRT6, and SIRT7, which were found to accumulate carbonylation-prone amino acids. Our data may help in finding new strategies to maintain and modify SIRT bioavailability in neurodegenerative disorders.

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Section: Resultsmentioning

confidence: 99%

The selective degradation of sirtuins via macroautophagy in the MPP+ model of Parkinson’s disease is promoted by conserved oxidation sites

et al. 2021

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“…The burden of HA RC-L1s could not only be an initiator of dopaminergic degeneration but also exacerbate it. In both a cell line model using human dopaminergic LUHMES cells and a mouse model of PD, L1s were activated in response to mitochondrial distress [ 19 ] and mitochondrial dysfunction is one the prominent molecular pathways involved in PD [ 35 ]. In another study utilizing a mouse model (Engrailed-1 heterozygotes), midbrain dopaminergic neurons degenerate, which coincides with an increase in L1 expression leading to DNA strand breaks, suggesting the protein Engrailed-1 in the adult represses L1s to protect these neurons [ 20 ].…”

Section: Discussionmentioning

confidence: 99%

“…Differential expression of retrotransposon mRNA and proteins, including those of L1s, has also been identified in several different neurological conditions, including Rett syndrome, amyotrophic lateral sclerosis, Alzheimer’s disease, ataxia telangiectasia, and Aicardi–Goutieres syndrome [ 11 , 13 , 14 , 15 , 16 , 17 , 18 ]. L1s have also been shown to be activated in cellular and mouse models of Parkinson’s disease (PD) [ 19 , 20 ]. Derepression of L1s in senescent cells and aged mice has been shown to activate age-associated inflammation, suggesting a potential role for these elements in age-associated disorders, which includes neurodegenerative diseases [ 21 ].…”

Section: Introductionmentioning

confidence: 99%

An Increased Burden of Highly Active Retrotransposition Competent L1s Is Associated with Parkinson’s Disease Risk and Progression in the PPMI Cohort

Pfaff

Bubb

Quinn

et al. 2020

IJMS

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Long interspersed element-1 (LINE-1/L1s) contributes 17% of the human genome with more than 1 million elements present; however, fewer than 100 of these have evidence for being retrotransposition competent (RC). In addition to those RC-L1s present in the reference genome, there are a small number of known non-reference L1 insertions that are also retrotransposition competent. L1 activity, whether through the potentially detrimental effects of their mRNA or protein expression or somatic retrotransposition events, has been linked to several neurological conditions. The polymorphic nature of both reference and non-reference RC-L1s in terms of their presence or absence will result in individuals harboring a different combination of these elements and it is currently unknown if this type of germline variation contributes to the risk of neurological disease. Here, we utilized whole-genome sequencing data from 178 healthy controls and 372 Parkinson’s disease (PD) subjects from the Parkinson’s Progression Markers Initiative (PPMI) to investigate the role of RC-L1s in PD. In the PPMI cohort, we identified 22 reference and 50 non-reference polymorphic RC-L1 loci. Focusing on 16 highly active RC-L1 loci, an increased burden of these elements (≥9) was associated with PD (OR 1.25, 95% CI 1.03–1.51, p = 0.02). In addition, we identified significant associations of progression markers of PD and the burden of highly active RC-L1s. This study has identified a novel type of genetic element associated with PD risk and disease progression.

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“…Scientists are also looking at novel targets and approaches against AD. Current research includes genetic instability, post-translational modification, and lipid metabolism related to long interspersed nuclear element-1, micro RNAs, and apolipoprotein E4, respectively [ 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 ]. Calmodulin-binding proteins associated with calcium homeostasis [ 92 ] have also been shown to have therapeutic potential against AD.…”

Section: Current Treatments For Alzheimer’s Diseasementioning

confidence: 99%

Therapeutic Potential of Human Stem Cell Implantation in Alzheimer’s Disease

Chan

Yanshree

Roy

et al. 2021

IJMS

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Alzheimer’s disease (AD) is a progressive debilitating neurodegenerative disease and the most common form of dementia in the older population. At present, there is no definitive effective treatment for AD. Therefore, researchers are now looking at stem cell therapy as a possible treatment for AD, but whether stem cells are safe and effective in humans is still not clear. In this narrative review, we discuss both preclinical studies and clinical trials on the therapeutic potential of human stem cells in AD. Preclinical studies have successfully differentiated stem cells into neurons in vitro, indicating the potential viability of stem cell therapy in neurodegenerative diseases. Preclinical studies have also shown that stem cell therapy is safe and effective in improving cognitive performance in animal models, as demonstrated in the Morris water maze test and novel object recognition test. Although few clinical trials have been completed and many trials are still in phase I and II, the initial results confirm the outcomes of the preclinical studies. However, limitations like rejection, tumorigenicity, and ethical issues are still barriers to the advancement of stem cell therapy. In conclusion, the use of stem cells in the treatment of AD shows promise in terms of effectiveness and safety.

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Retrotransposon activation by distressed mitochondria in neurons

Cited by 22 publications

References 29 publications

The selective degradation of sirtuins via macroautophagy in the MPP+ model of Parkinson’s disease is promoted by conserved oxidation sites

The selective degradation of sirtuins via macroautophagy in the MPP+ model of Parkinson’s disease is promoted by conserved oxidation sites

An Increased Burden of Highly Active Retrotransposition Competent L1s Is Associated with Parkinson’s Disease Risk and Progression in the PPMI Cohort

Therapeutic Potential of Human Stem Cell Implantation in Alzheimer’s Disease

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