DOPAnization of tyrosine in α-synuclein by tyrosine hydroxylase leads to the formation of oligomers

Jin, Mingyue; Matsumoto, Sakiko; Ayaki, Takashi; Yamakado, Hodaka; Taguchi, Tomoyuki; Togawa, Natsuko; Konno, Ayumu; Hirai, Hirokazu; Nakajima, Hiroshi; Komai, Shoji; Ishida, Ryuichi; Chiba, Syuhei; Takahashi, Ryōsuke; Takao, Toshifumi; Hirotsune, Shinji

doi:10.1038/s41467-022-34555-4

Cited by 11 publications

(7 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recently, it has been shown that the activity of tyrosine hydroxylase, an enzyme specifically expressed in catecholamine-containing neurons, can induce the hydroxylation of Tyr 136 in the α-Syn sequence. This DOPAnization promoted the α-Syn oligomerization, which may play a pathogenic role in dopaminergic neurodegeneration [ 109 ]. The Y136-DOPA-Syn signal was detected at the striatonigral axon terminals of aged A53T Tg mice and patients with PD or MSA but not in controls.…”

Section: Alpha-synuclein Oligomersmentioning

confidence: 99%

“…The Y136-DOPA-Syn signal was detected at the striatonigral axon terminals of aged A53T Tg mice and patients with PD or MSA but not in controls. This suggests that DOPAnization of α-Syn may occur during the disease progression rather than initiating the pathological process, but in any case, it might contribute to the selective loss of dopaminergic neurons in synucleinopathies [ 109 ].…”

Section: Alpha-synuclein Oligomersmentioning

confidence: 99%

See 1 more Smart Citation

Alpha Synuclein: Neurodegeneration and Inflammation

Forloni

2023

IJMS

View full text Add to dashboard Cite

Alpha-Synuclein (α-Syn) is one of the most important molecules involved in the pathogenesis of Parkinson’s disease and related disorders, synucleinopathies, but also in several other neurodegenerative disorders with a more elusive role. This review analyzes the activities of α-Syn, in different conformational states, monomeric, oligomeric and fibrils, in relation to neuronal dysfunction. The neuronal damage induced by α-Syn in various conformers will be analyzed in relation to its capacity to spread the intracellular aggregation seeds with a prion-like mechanism. In view of the prominent role of inflammation in virtually all neurodegenerative disorders, the activity of α-Syn will also be illustrated considering its influence on glial reactivity. We and others have described the interaction between general inflammation and cerebral dysfunctional activity of α-Syn. Differences in microglia and astrocyte activation have also been observed when in vivo the presence of α-Syn oligomers has been combined with a lasting peripheral inflammatory effect. The reactivity of microglia was amplified, while astrocytes were damaged by the double stimulus, opening new perspectives for the control of inflammation in synucleinopathies. Starting from our studies in experimental models, we extended the perspective to find useful pointers to orient future research and potential therapeutic strategies in neurodegenerative disorders.

show abstract

Section: Alpha-synuclein Oligomersmentioning

confidence: 99%

Section: Alpha-synuclein Oligomersmentioning

confidence: 99%

Alpha Synuclein: Neurodegeneration and Inflammation

Forloni

2023

IJMS

View full text Add to dashboard Cite

show abstract

“…As for tyrosine oxidation in regard to ɑ-syn and PD, it is also relevant that the oxidation of free tyrosine produces L-DOPA. Indeed, DOPAnization of tyrosine in α-syn by tyrosine hydroxylase (TH) leads to the formation of oligomers (Jin et al 2022 ). L-DOPA has pro-oxidant properties and can modify ɑ-syn (Post et al 2018 ) and so increase the sensitivity to oxidative stress and degeneration of catecholaminergic neurons (Lipski et al 2011 ).…”

Section: A Closer Look At ɑ-Synuclein and Lbsmentioning

confidence: 99%

Lewy bodies, iron, inflammation and neuromelanin: pathological aspects underlying Parkinson’s disease

Riederer

Nagatsu

Youdim³

et al. 2023

J Neural Transm

View full text Add to dashboard Cite

Since the description of some peculiar symptoms by James Parkinson in 1817, attempts have been made to define its cause or at least to enlighten the pathology of “Parkinson’s disease (PD).” The vast majority of PD subtypes and most cases of sporadic PD share Lewy bodies (LBs) as a characteristic pathological hallmark. However, the processes underlying LBs generation and its causal triggers are still unknown. ɑ-Synuclein (ɑ-syn, encoded by the SNCA gene) is a major component of LBs, and SNCA missense mutations or duplications/triplications are causal for rare hereditary forms of PD. Thus, it is imperative to study ɑ-syn protein and its pathology, including oligomerization, fibril formation, aggregation, and spreading mechanisms. Furthermore, there are synergistic effects in the underlying pathogenic mechanisms of PD, and multiple factors—contributing with different ratios—appear to be causal pathological triggers and progression factors. For example, oxidative stress, reduced antioxidative capacity, mitochondrial dysfunction, and proteasomal disturbances have each been suggested to be causal for ɑ-syn fibril formation and aggregation and to contribute to neuroinflammation and neural cell death. Aging is also a major risk factor for PD. Iron, as well as neuromelanin (NM), show age-dependent increases, and iron is significantly increased in the Parkinsonian substantia nigra (SN). Iron-induced pathological mechanisms include changes of the molecular structure of ɑ-syn. However, more recent PD research demonstrates that (i) LBs are detected not only in dopaminergic neurons and glia but in various neurotransmitter systems, (ii) sympathetic nerve fibres degenerate first, and (iii) at least in “brain-first” cases dopaminergic deficiency is evident before pathology induced by iron and NM. These recent findings support that the ɑ-syn/LBs pathology as well as iron- and NM-induced pathology in “brain-first” cases are important facts of PD pathology and via their interaction potentiate the disease process in the SN. As such, multifactorial toxic processes posted on a personal genetic risk are assumed to be causal for the neurodegenerative processes underlying PD. Differences in ratios of multiple factors and their spatiotemporal development, and the fact that common triggers of PD are hard to identify, imply the existence of several phenotypical subtypes, which is supported by arguments from both the “bottom-up/dual-hit” and “brain-first” models. Therapeutic strategies are necessary to avoid single initiation triggers leading to PD.

show abstract

“…Calpain over-activation is observed in various neurological disorders and injuries such as PD, AD, muscular dystrophy, traumatic brain injury, and spinal cord injury. Its activity increases with mutated α-syn [115]. Activation of the RhoA pathway plays a crucial role in cell signaling in both neurons and glial cells [116][117][118].…”

Section: Calpain's Role In Neuroinflammation and Pdmentioning

confidence: 99%

Insights into Calpain Activation and Rho-ROCK Signaling in Parkinson’s Disease and Aging

Gathings,

Zaman,

Banik

et al. 2024

Biomedicines

View full text Add to dashboard Cite

Parkinson’s disease (PD), a progressive neurodegenerative disease, has no cure, and current therapies are not effective at halting disease progression. The disease affects mid-brain dopaminergic neurons and, subsequently, the spinal cord, contributing to many debilitating symptoms associated with PD. The GTP-binding protein, Rho, plays a significant role in the cellular pathology of PD. The downstream effector of Rho, Rho-associated kinase (ROCK), plays multiple functions, including microglial activation and induction of inflammatory responses. Activated microglia have been implicated in the pathology of many neurodegenerative diseases, including PD, that initiate inflammatory responses, leading to neuron death. Calpain expression and activity is increased following glial activation, which triggers the Rho-ROCK pathway and induces inflammatory T cell activation and migration as well as mediates toxic α-synuclein (α-syn) aggregation and neuron death, indicating a pivotal role for calpain in the inflammatory and degenerative processes in PD. Increased calpain activity and Rho-ROCK activation may represent a new mechanism for increased oxidative damage in aging. This review will summarize calpain activation and the role of the Rho-ROCK pathway in oxidative stress and α-syn aggregation, their influence on the neurodegenerative process in PD and aging, and possible strategies and research directions for therapeutic intervention.

show abstract

DOPAnization of tyrosine in α-synuclein by tyrosine hydroxylase leads to the formation of oligomers

Cited by 11 publications

References 60 publications

Alpha Synuclein: Neurodegeneration and Inflammation

Alpha Synuclein: Neurodegeneration and Inflammation

Lewy bodies, iron, inflammation and neuromelanin: pathological aspects underlying Parkinson’s disease

Insights into Calpain Activation and Rho-ROCK Signaling in Parkinson’s Disease and Aging

Contact Info

Product

Resources

About