Doxycycline inhibits α-synuclein-associated pathologies in vitro and in vivo

Dominguez-Meijide, Antonio; Parrales, Valeria; Vasili, Eftychia; González‐Lizárraga, Florencia; König, Anika; Lázaro, Diana F.; Lannuzel, Annie; Haı̈k, Stéphane; Del‐Bel, Elaine; Chehı́n, Rosana; Raisman‐Vozari, Rita; Michel, Patrick P.; Bizat, Nicolas; Outeiro, Tiago F.

doi:10.1016/j.nbd.2021.105256

Cited by 51 publications

(55 citation statements)

References 102 publications

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“…α-syn can misfold and aggregate under various factors, including raised calcium concentration, oxidative stress, gene mutations, and interactions with many other proteins [12]. Aggregation and propagation of misfolded α-syn in the brain are involved in the pathogenesis of neurodegenerative diseases, especially in Parkinson's disease cases [13,14]. In our earlier work, we demonstrated that anesthesia and surgery increased α-syn oligomerization and disturbed neurotransmitter homeostasis in the hippocampus of aged rats, while exosome α-syn release into the plasma of postoperative delirium (POD) patients with hip fractures was significantly higher compared with non-POD cases [15,16].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of α‐Synuclein Accumulation Improves Neuronal Apoptosis and Delayed Postoperative Cognitive Recovery in Aged Mice

Yuan

et al. 2021

Oxidative Medicine and Cellular Longevity

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Delayed neurocognitive recovery (dNCR) is a major complication after anesthesia and surgery in older adults. Alpha-synuclein (α-syn; encoded by the gene, SNCA) has recently been shown to play an important role in hippocampus-dependent working memory. Aggregated forms of α-syn are associated with multiple neurotoxic mechanisms, such as mitochondrial dysfunction and cell death. In this study, we found that blocking α-syn improved both mitochondrial function and mitochondria-dependent neuronal apoptosis in a mouse model of dNCR. Various forms of α-syn (including total α-syn, phosphorylated-Ser129-α-syn, and oligomers) were upregulated in hippocampal tissue and extracted mitochondria after surgical challenge. Clenbuterol is a novel transcription modulator of Scna. Clenbuterol significantly attenuated surgery-induced progressive accumulation of various toxic α-syn forms in the hippocampus, as well as mitochondrial damage and memory deficits in aged mice following surgery. We also observed excessive mitochondrial α-syn accumulation and increased mitochondria-mediated apoptosis in vitro using nerve growth factor-differentiated PC12 cells and primary hippocampal neurons exposed to lipopolysaccharide. To further validate the neuroprotective effect of α-syn inhibition, we used a lentiviral Snca-shRNA (Lv-shSnca) to knockdown Snca. Of note, Lv-shSnca transfection significantly inhibited neuronal apoptosis mediated by the mitochondrial apoptosis pathway in neurons exposed to lipopolysaccharide. This α-syn inhibition improved the disruption to mitochondrial morphology and function, as well as decreased levels of apoptosis. Our results suggest that targeting pathological α-syn may achieve neuroprotection through regulation of mitochondrial homeostasis and suppression of apoptosis in the aged hippocampus, further strengthening the therapeutic potential of targeting α-syn for dNCR.

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Section: Introductionmentioning

confidence: 99%

Inhibition of α‐Synuclein Accumulation Improves Neuronal Apoptosis and Delayed Postoperative Cognitive Recovery in Aged Mice

Yuan

et al. 2021

Oxidative Medicine and Cellular Longevity

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“…Furthermore, this antibiotic lowered the production of reactive oxygen species by mitochondria. These results demonstrate that doxycycline treatment [51] may be an effective strategy against PD and other synucleinopathies [52,53]. A wide range of approaches were applied by molecular, genetic, and chemical manipulations of gene function, i.e., using transgenic overexpression of exogenous human disease-related proteins, mutagenesis (transposonbased insertion, deletion libraries, etc.…”

Section: Discussionmentioning

confidence: 86%

“…An example of this approach's efficiency in potential drug testing was recently proven in a study of doxycycline as a potential treatment for PD. Dominguez-Meijide and coauthors [51] used a C. elegans model of PD and found that doxycycline induced a cellular redistribution of α-synuclein aggregates and decreased their number and size. Furthermore, this antibiotic lowered the production of reactive oxygen species by mitochondria.…”

Section: Discussionmentioning

confidence: 99%

Invertebrate Models Untangle the Mechanism of Neurodegeneration in Parkinson’s Disease

Surguchov

2021

Cells

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Parkinson’s disease (PD) is the second most common neurodegenerative disease, afflicting ~10 million people worldwide. Although several genes linked to PD are currently identified, PD remains primarily an idiopathic disorder. Neuronal protein α-synuclein is a major player in disease progression of both genetic and idiopathic forms of PD. However, it cannot alone explain underlying pathological processes. Recent studies demonstrate that many other risk factors can accelerate or further worsen brain dysfunction in PD patients. Several PD models, including non-mammalian eukaryotic organisms, have been developed to identify and characterize these factors. This review discusses recent findings in three PD model organisms, i.e., yeast, Drosophila, and Caenorhabditis elegans, that opened new mechanisms and identified novel contributors to this disorder. These non-mammalian models share many conserved molecular pathways and cellular processes with humans. New players affecting PD pathogenesis include previously unknown genes/proteins, novel signaling pathways, and low molecular weight substances. These findings might respond to the urgent need to discover novel drug targets for PD treatment and new biomarkers for early diagnostics of this disease. Since the study of neurodegeneration using simple eukaryotic organisms brought a huge amount of information, we include only the most recent or the most important relevant data.

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“…As Paracelsus said "dosis sola facit venenum". [41,[185][186][187][188][189][190][191][192][193]. mtUPR activation [95,141] Inhibit cancer proliferation [40,134] Mitochondrial protection from ischemia [223,227] Promote heteroplasmy [156] Mitochondrial biogenesis impairment [258] Mitochondrial respiratory chain activity reduction […”

Section: Discussionmentioning

confidence: 99%

“…In fact, aggregate forms of αSyn can self-propagate within neurons and to interconnected neural networks throughout the nervous system in a prion-like manner, resulting in the spread of the pathology across the brain and the progression of PD [184]. Several studies have proposed tetracyclines and derivatives, such as doxycycline and minocycline, as neuroprotector antibiotics through several mechanisms: their anti-inflammatory properties [41]; their ability to protect dopaminergic neurons in the substantia nigra [185]; the fact that they regulate the glial response in induced PD animal models [186]; their capacity to both inhibit fibril formation of amyloid beta (Aβ) [187], prion protein (PrP) [188,189], β-microglobulin [190] and aSyn [191] and to block amyloid size and aggregation [192,193].…”

Section: Neurodegenerationmentioning

confidence: 99%

Mitochondria and Antibiotics: For Good or for Evil?

et al. 2021

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The discovery and application of antibiotics in the common clinical practice has undeniably been one of the major medical advances in our times. Their use meant a drastic drop in infectious diseases-related mortality and contributed to prolonging human life expectancy worldwide. Nevertheless, antibiotics are considered by many a double-edged sword. Their extensive use in the past few years has given rise to a global problem: antibiotic resistance. This factor and the increasing evidence that a wide range of antibiotics can damage mammalian mitochondria, have driven a significant sector of the medical and scientific communities to advise against the use of antibiotics for purposes other to treating severe infections. Notwithstanding, a notorious number of recent studies support the use of these drugs to treat very diverse conditions, ranging from cancer to neurodegenerative or mitochondrial diseases. In this context, there is great controversy on whether the risks associated to antibiotics outweigh their promising beneficial features. The aim of this review is to provide insight in the topic, purpose for which the most relevant findings regarding antibiotic therapies have been discussed.

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Doxycycline inhibits α-synuclein-associated pathologies in vitro and in vivo

Cited by 51 publications

References 102 publications

Inhibition of α‐Synuclein Accumulation Improves Neuronal Apoptosis and Delayed Postoperative Cognitive Recovery in Aged Mice

Inhibition of α‐Synuclein Accumulation Improves Neuronal Apoptosis and Delayed Postoperative Cognitive Recovery in Aged Mice

Invertebrate Models Untangle the Mechanism of Neurodegeneration in Parkinson’s Disease

Mitochondria and Antibiotics: For Good or for Evil?

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