Dopamine Oxidation Products as Mitochondrial Endotoxins, a Potential Molecular Mechanism for Preferential Neurodegeneration in Parkinson’s Disease

Biosa, Alice; Arduini, Irene; Soriano, María Eugenia; Giorgio, Valentina; Bernardi, Paolo; Bisaglia, Marco; Bubacco, Luigi

doi:10.1021/acschemneuro.8b00276

Cited by 46 publications

(41 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Oxidative stress has been much more elusive, and cellular processes contributing to it have been vaguely defined. The dopaminergic neurons that die in Parkinson’s disease are unusually prone to mutations in mitochondrial quality-control factors, such as Parkin and PINK1 [1,2], to mitochondrial toxins like rotenone [3], and to dopamine oxidation products [4,5,6,7,8,9,10,11]. As a consequence, Parkinson’s disease may offer a unique window into the role of oxidative stress in neurodegenerative diseases generally.…”

Section: Introductionmentioning

confidence: 99%

“…In the context of Parkinson’s disease (PD), the unique vulnerability of dopamine neurons to oxidative stress has received considerable attention. Much of that has focused on dopamine, the defining component of dopaminergic neurons, and on potentially toxic products formed by its oxidation [6,7,8,9,10,11]. Although candidate toxins have been elusive, we recently described hypochlorite-oxidized cysteinyl-dopamine (HOCD), a cytotoxin formed by exposing cysteinyl-dopamine to hypochlorite [4].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Are Proteinopathy and Oxidative Stress Two Sides of the Same Coin?

Mehta

Marwah

Njus

2019

Cells

View full text Add to dashboard Cite

Parkinson’s disease, like other neurodegenerative diseases, exhibits two common features: Proteinopathy and oxidative stress, leading to protein aggregation and mitochondrial damage respectively. Because both protein aggregates and dysfunctional mitochondria are eliminated by autophagy, we suggest that inadequate clearance may couple the two phenomena. If a neuron’s autophagy machinery is overwhelmed, whether by excessive oxidative stress or by excessive protein aggregation, protein aggregates and dysfunctional mitochondria will both accumulate. Parkinson’s disease may provide a unique window into this because there is evidence that both sides contribute. Mutations amplifying the aggregation of α-synuclein are associated with Parkinson’s disease. Likewise, mutations in Parkin and PINK1, proteins involved in mitophagy, suggest that impaired mitochondrial clearance is also a contributing factor. Many have suggested that dopamine oxidation products lead to oxidative stress accounting for the dopaminergic selectivity of the disease. We have presented evidence for the specific involvement of hypochlorite-oxidized cysteinyl-dopamine (HOCD), a redox-cycling benzothiazine derivative. While toxins like 6-hydroxydopamine and 1-methyl-4-phenyl pyridinium (MPP+) have been used to study mitochondrial involvement in Parkinson’s disease, HOCD may provide a more physiologically relevant approach. Understanding the role of mitochondrial dysfunction and oxidative stress in Parkinson’s disease and their relation to α-synuclein proteinopathy is important to gain a full picture of the cause, especially for the great majority of cases which are idiopathic.

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Are Proteinopathy and Oxidative Stress Two Sides of the Same Coin?

Mehta

Marwah

Njus

2019

Cells

View full text Add to dashboard Cite

show abstract

“…The etiology of PD includes a number of potential factors, such as age, genetic aberrations, or environmentally-derived and endogenous neurotoxins [ 1 ]. The environmental exposures or inherited mutation in metabolic pathways might cause the production of toxic substances, such as reactive oxygen species (ROS), from endogenous dopamine or environmentally-derived neurotoxins [ 3 , 4 , 5 ]. Overproduction of ROS leads to mitochondrial dysfunction and abnormal processing of cellular proteins and triggers the apoptosis of dopaminergic neurons.…”

Section: Introductionmentioning

confidence: 99%

Aqueous Extract of Davallia mariesii Attenuates 6-Hydroxydopamine-Induced Oxidative Damage and Apoptosis in B35 Cells Through Inhibition of Caspase Cascade and Activation of PI3K/AKT/GSK-3β Pathway

Chang

Cheng

et al. 2018

Nutrients

View full text Add to dashboard Cite

The medicinal ferns of Polydiaceae and Davalliaceae species are called “Gusuibu” by Chinese physicians and used as antiaging dietary medicines. Our previous report revealed that Drynaria fortunei (Polydiaceae) protected against 6-hydroxydopamine (6-OHDA)-induced oxidative damage via the PI3K/AKT pathway in B35 neuroblastoma cells. The present study compares the antioxidant phytoconstituent contents and radical scavenging capacities of five Davalliaceae species. The further aim was to clarify the protective mechanism of Davallia mariesii (DM) against 6-OHDA-induced oxidative damage and apoptosis in B35 cells. The results show that Araiostegia perdurans (AP) and DM extracts have better radical scavenging capacities against 1,1-diphenyl-2-picryhydrazyl (DPPH) and reactive oxygen species (ROS) than other Davalliaceae species. However, only DM extract inhibited 6-OHDA autoxidation under cell-free systems and increased cell viability, compared to B35 cells solely exposed to 6-OHDA. DM extract decreased apoptosis and restored mitochondrial expression in 6-OHDA-treated B35 cells. Additional data indicated that DM extract decreased intracellular ROS and nitric oxide levels generated by 6-OHDA exposure. DM extract also restored glutathione (GSH) levels and the activities of glutathione peroxidase and reductase, and then decreased the elevated malondialdehyde (MDA) levels. Finally, DM extract regulated the protein expression of the caspase cascade and PI3K/AKT/GSK-3β pathways. These results suggest that the protective mechanism of DM extract against 6-OHDA-induced oxidative damage and apoptosis might be related to its radical scavenging capacity, maintaining the mitochondrial function to inhibit the Bcl-2/caspase cascade pathway and activating intracellular antioxidant defenses (GSH recycling, HO-1 and NQO-1) by modulating the activation of the PI3K/AKT/GSK-3β pathway.

show abstract

“…In the absence of feedback inhibition, the DA synthesis flux would become unaffected by the accumulating cytosolic DA at full vesicular pools, and the steady state level of cytosolic DA would be determined by the balance between the unconstrained synthesis rate and DA metabolization by monoamine oxidase. However, DA and other CAs are redox-active and considered neurotoxic at increased levels 50 , which may be a reason for the evolution of a strong feedback inhibition of TH, not found for serotonin and TPH. The presence of a flexible N-terminal region in TH is important for the stabilization of DA feedback inhibition and allows for an additional level of regulation, as the S40 site enables signalling pathways to modulate the feedback inhibitory strength of CAs.…”

Section: Discussionmentioning

confidence: 99%

The Structure of Human Tyrosine Hydroxylase Reveals the Mechanism for Feedback Inhibition by Dopamine

Valpuesta¹,

Bueno-Carrasco²,

Cuéllar³

et al. 2020

Preprint

View full text Add to dashboard Cite

Tyrosine hydroxylase (TH) is a highly regulated enzyme that catalyses the rate-limiting step in the biosynthesis of dopamine (DA) and other catecholamines. Mutations and dysfunction in this enzyme lead to DA deficiency and parkinsonisms of different severity. An understanding of TH deficiency at the level of structure and stability has been lacking to date, as only structures of truncated TH forms have been available. Here, we used cryoEM to determine the first high-resolution structure of full-length human tetrameric TH in the absence (3.4 Å) and presence (3.8 Å) of the end-product and feedback inhibitor DA bound to the active site. We show that upon DA binding, an α-helix (residues 39-59) included within the flexible N-terminal tail of the regulatory domain, is internalized in the active site. The observed structural changes reveal the molecular basis of the inhibitory and stabilizing DA effect, reversible by TH S40-phosphorylation, which are crucial regulatory mechanisms for catecholamine and TH homeostasis.

show abstract

Dopamine Oxidation Products as Mitochondrial Endotoxins, a Potential Molecular Mechanism for Preferential Neurodegeneration in Parkinson’s Disease

Cited by 46 publications

References 45 publications

Are Proteinopathy and Oxidative Stress Two Sides of the Same Coin?

Are Proteinopathy and Oxidative Stress Two Sides of the Same Coin?

Aqueous Extract of Davallia mariesii Attenuates 6-Hydroxydopamine-Induced Oxidative Damage and Apoptosis in B35 Cells Through Inhibition of Caspase Cascade and Activation of PI3K/AKT/GSK-3β Pathway

The Structure of Human Tyrosine Hydroxylase Reveals the Mechanism for Feedback Inhibition by Dopamine

Contact Info

Product

Resources

About