DJ-1 Protein and Its Role in the Development of Parkinson’s Disease: Studies on Experimental Models

Buneeva, O. A.; Медведев, А.Е.

doi:10.1134/s000629792106002x

Cited by 15 publications

(8 citation statements)

References 99 publications

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“…Thus, alterations in mitochondrial function may lead to an increase of ROS levels above a toxicity threshold resulting in potentially unwanted oxidative consequences and even cell death . For instance, it has been found that mitochondrial damage in PD might be caused by complex I of the electron transport chain (ETC) dysfunction, , a complex to which the DJ-1 protein directly binds . In addition, several toxins (rotenone, paraquat or MPTP) able to inhibit its activity are commonly used to generate animal and cell models of idiopathic PD. , Since PD model cells showed a decrease in active mitochondria, we aimed to study the consequence of that reduction in ROS levels.…”

Section: Resultsmentioning

confidence: 99%

Disease-Modifying Effects of Vincamine Supplementation in Drosophila and Human Cell Models of Parkinson’s Disease Based on DJ-1 Deficiency

Sanz

Solana-Manrique

Paricio

2023

ACS Chem. Neurosci.

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Parkinson's disease (PD) is an incurable neurodegenerative disorder caused by the selective loss of dopaminergic neurons in the substantia nigra pars compacta. Current therapies are only symptomatic and are not able to stop or delay its progression. In order to search for new and more effective therapies, our group carried out a high-throughput screening assay, identifying several candidate compounds that are able to improve locomotor ability in DJ-1β mutant flies (a Drosophila model of familial PD) and reduce oxidative stress (OS)-induced lethality in DJ-1-deficient SH-SY5Y human cells. One of them was vincamine (VIN), a natural alkaloid obtained from the leaves of Vinca minor. Our results showed that VIN is able to suppress PD-related phenotypes in both Drosophila and human cell PD models. Specifically, VIN reduced OS levels in PD model flies. Besides, VIN diminished OSinduced lethality by decreasing apoptosis, increased mitochondrial viability, and reduced OS levels in DJ-1-deficient human cells. In addition, our results show that VIN might be exerting its beneficial role, at least partially, by the inhibition of voltage-gated sodium channels. Therefore, we propose that these channels might be a promising target in the search for new compounds to treat PD and that VIN represents a potential therapeutic treatment for the disease.

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Section: Resultsmentioning

confidence: 99%

Disease-Modifying Effects of Vincamine Supplementation in Drosophila and Human Cell Models of Parkinson’s Disease Based on DJ-1 Deficiency

Sanz

Solana-Manrique

Paricio

2023

ACS Chem. Neurosci.

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“…Thus, alterations in mitochondrial function may lead to an increase of ROS levels above a toxicity threshold resulting in potentially unwanted oxidative consequences and even cell death (Zorov et al, 2014). For instance, it has been found that mitochondrial damage in PD might be caused by complex I of the electron transport chain (ETC) dysfunction (Aryal & Lee, 2019; González-Rodríguez et al, 2021), a complex to which the DJ-1 protein directly binds (Buneeva & Medvedev, 2021). In addition, several toxins (rotenone, paraquat or MPTP) able to inhibit its activity are commonly used to generate animal and cell models of idiopathic PD (Aryal & Lee, 2019; Wen et al, 2020).…”

Section: Resultsmentioning

confidence: 99%

Disease-modifying effects of Vincamine supplementation inDrosophilaand human cell models of Parkinson’s disease

Sanz

Solana-Manrique

Paricio

2022

Preprint

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Parkinson's disease (PD) is an incurable neurodegenerative disorder caused by the selective loss of dopaminergic neurons in thesubstantia nigra pars compacta. Current therapies are only symptomatic, and are not able to stop or delay its progression. In order to search new and more effective therapies, our group carried out a high-throughput screening assay, identifying several candidate compounds able to suppress motor defects inDJ-1βmutant flies (aDrosophilamodel of familial PD) and to reduce oxidative stress (OS)-induced lethality inDJ-1-deficient SH-SY5Y human cells. One of them was vincamine (VIN), a natural alkaloid obtained from the leaves of Vinca minor. Our results showed that VIN is able to suppress PD-related phenotypes in bothDrosophilaand human cell PD models. Specifically, VIN reduced OS levels in PD model flies. Besides, VIN diminished OS-induced lethality by decreasing apoptosis, increased mitochondrial viability and reduced OS levels inDJ-1-deficient human cells. In addition, we have demonstrated that VIN is able to exert its beneficial role, at least partially, by the inhibition of voltage-gated Na+channels. Therefore, we propose that these channels might be a promising target in the search for new compounds to treat PD, and that VIN constitutes a potential therapeutic treatment for the disease.

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“…Isatin is an endogenous indole exhibiting various biological and pharmacological activities [ 197 ]. By interacting with numerous intracellular isatin-binding proteins, isatin can act as a regulator of complex protein networks in normal and pathological states [ 93 , 115 , 197 ].…”

Section: Discussionmentioning

confidence: 99%

“…DJ-1, also known as Parkinson disease protein 7, is a multifunctional protein ubiquitously expressed in cells and tissues and exhibiting both catalytic (as protein deglycase, EC 3.5.1.124) and numerous noncatalytic activities [ 93 , 94 , 95 ].…”

Section: Atypical Ubiquitination Of the Components Of Lewy Bodies: Al...mentioning

confidence: 99%

Atypical Ubiquitination and Parkinson’s Disease

Buneeva

Медведев

2022

IJMS

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Ubiquitination (the covalent attachment of ubiquitin molecules to target proteins) is one of the main post-translational modifications of proteins. Historically, the type of polyubiquitination, which involves K48 lysine residues of the monomeric ubiquitin, was the first studied type of ubiquitination. It usually targets proteins for their subsequent proteasomal degradation. All the other types of ubiquitination, including monoubiquitination; multi-monoubiquitination; and polyubiquitination involving lysine residues K6, K11, K27, K29, K33, and K63 and N-terminal methionine, were defined as atypical ubiquitination (AU). Good evidence now exists that AUs, participating in the regulation of various cellular processes, are crucial for the development of Parkinson’s disease (PD). These AUs target various proteins involved in PD pathogenesis. The K6-, K27-, K29-, and K33-linked polyubiquitination of alpha-synuclein, the main component of Lewy bodies, and DJ-1 (another PD-associated protein) is involved in the formation of insoluble aggregates. Multifunctional protein kinase LRRK2 essential for PD is subjected to K63- and K27-linked ubiquitination. Mitophagy mediated by the ubiquitin ligase parkin is accompanied by K63-linked autoubiquitination of parkin itself and monoubiquitination and polyubiquitination of mitochondrial proteins with the formation of both classical K48-linked ubiquitin chains and atypical K6-, K11-, K27-, and K63-linked polyubiquitin chains. The ubiquitin-specific proteases USP30, USP33, USP8, and USP15, removing predominantly K6-, K11-, and K63-linked ubiquitin conjugates, antagonize parkin-mediated mitophagy.

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DJ-1 Protein and Its Role in the Development of Parkinson’s Disease: Studies on Experimental Models

Cited by 15 publications

References 99 publications

Disease-Modifying Effects of Vincamine Supplementation in Drosophila and Human Cell Models of Parkinson’s Disease Based on DJ-1 Deficiency

Disease-Modifying Effects of Vincamine Supplementation in Drosophila and Human Cell Models of Parkinson’s Disease Based on DJ-1 Deficiency

Disease-modifying effects of Vincamine supplementation inDrosophilaand human cell models of Parkinson’s disease

Atypical Ubiquitination and Parkinson’s Disease

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