Rhododendrin-Induced RNF146 Expression via Estrogen Receptor β Activation is Cytoprotective Against 6-OHDA-Induced Oxidative Stress

Ring finger protein 146 (RNF146) is an E3 ubiquitin ligase whose activity prevents poly (ADP-ribose) polymerase 1 (PARP1)-dependent neurodegeneration in Parkinson’s disease (PD). Previously, we reported that rhododendrin is a chemical inducer that increases RNF146 expression. However, the molecular mechanism of rhododendrin-induced RNF146 expression is largely unknown and its translational application for the treatment of Parkinson’s disease remains unexplored. Here we found that rhododendrin increased RNF146 expression via estrogen receptor β (ERβ) activation. Rhododendrin stimulated ERβ nuclear translocation and binding to the RNF146 promoter, thereby enhancing its transcription. Rhododendrin is cytoprotective against 6-hydroxydopamine (6-OHDA)-induced cell death, which is largely dependent on ERβ activity and RNF146 expression. Finally, we demonstrated that rhododendrin treatment resulted in RNF146 expression in dopaminergic neurons in mice. Moreover, dopaminergic neuron viability was markedly enhanced by pretreatment with rhododendrin in 6-OHDA-induced mouse models for PD. Our findings indicate that estrogen receptor activation plays a neuroprotective role and that rhododendrin could be a potential therapeutic agent in preventing PARP1-dependent dopaminergic cell loss in PD.

Download Full-text

PAX6 expression may be protective against dopaminergic cell loss in Parkinson's disease

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527314666150821101757 ◽

2016 ◽

Vol 15 (1) ◽

pp. 73-79 ◽

Cited By ~ 6

Author(s):

Meghan G. Thomas ◽

Caitlyn Welch ◽

Leah Stone ◽

Peter Allan ◽

Roger A. Barker ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Cell Loss ◽

Pax6 Expression ◽

Dopaminergic Cell

Download Full-text

Neuroprotection in Parkinson’s disease: facts and hopes

Journal of Neural Transmission ◽

10.1007/s00702-019-02115-8 ◽

2019 ◽

Vol 127 (5) ◽

pp. 821-829 ◽

Cited By ~ 5

Author(s):

András Salamon ◽

Dénes Zádori ◽

László Szpisjak ◽

Péter Klivényi ◽

László Vécsei

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Cell Loss ◽

Substantia Nigra Pars Compacta ◽

Neuroprotective Agents ◽

Dopaminergic Cell ◽

Pathological Mechanism ◽

Positive Results

AbstractParkinson’s disease (PD) is the second most common neurodegenerative disease worldwide. Behind the symptoms there is a complex pathological mechanism which leads to a dopaminergic cell loss in the substantia nigra pars compacta. Despite the strong efforts, curative treatment has not been found yet. To prevent a further cell death, numerous molecules were tested in terms of neuroprotection in preclinical (in vitro, in vivo) and in clinical studies as well. The aim of this review article is to summarize our knowledge about the extensively tested neuroprotective agents (Search period: 1991–2019). We detail the underlying pathological mechanism and summarize the most important results of the completed animal and clinical trials. Although many positive results have been reported in the literature, there is still no evidence that any of them should be used in clinical practice (Cochrane analysis was performed). Therefore, further studies are needed to better understand the pathomechanism of PD and to find the optimal neuroprotective agent(s).

Download Full-text

Granulocyte macrophage-colony stimulating factor protects against substantia nigra dopaminergic cell loss in an environmental toxin model of Parkinson's disease

Neurobiology of Disease ◽

10.1016/j.nbd.2011.02.011 ◽

2011 ◽

Vol 43 (1) ◽

pp. 99-112 ◽

Cited By ~ 34

Author(s):

E.N. Mangano ◽

S. Peters ◽

D. Litteljohn ◽

R. So ◽

C. Bethune ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Substantia Nigra ◽

Cell Loss ◽

Colony Stimulating Factor ◽

Dopaminergic Cell ◽

Environmental Toxin ◽

Macrophage Colony Stimulating Factor ◽

Macrophage Colony ◽

Stimulating Factor

Download Full-text

The estrogen receptor β-PI3K/Akt pathway mediates the cytoprotective effects of tocotrienol in a cellular Parkinson's disease model

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease ◽

10.1016/j.bbadis.2014.04.008 ◽

2014 ◽

Vol 1842 (9) ◽

pp. 1303-1312 ◽

Cited By ~ 32

Author(s):

Kazuhiro Nakaso ◽

Naoko Tajima ◽

Yosuke Horikoshi ◽

Masato Nakasone ◽

Takehiko Hanaki ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Estrogen Receptor ◽

Disease Model ◽

Estrogen Receptor Β ◽

Akt Pathway

Download Full-text

Neuroprotective Mechanism of Mitochondrial Ferritin on 6-Hydroxydopamine–Induced Dopaminergic Cell Damage: Implication for Neuroprotection in Parkinson's Disease

Antioxidants and Redox Signaling ◽

10.1089/ars.2009.3018 ◽

2010 ◽

Vol 13 (6) ◽

pp. 783-796 ◽

Cited By ~ 51

Author(s):

Zhen-Hua Shi ◽

Guangjun Nie ◽

Xiang-Lin Duan ◽

Tracey Rouault ◽

Wen-Shuang Wu ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Cell Damage ◽

Dopaminergic Cell ◽

6 Hydroxydopamine

Download Full-text

Association Between Decreased Srpk3 Expression And An Increase In Substantia Nigra Alpha-Synuclein Levels In An MPTP-Induced Parkinson’s Disease Mouse Model

10.21203/rs.3.rs-1207279/v1 ◽

2022 ◽

Author(s):

Min Hyung Seo ◽

Sujung Yeo

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Substantia Nigra ◽

Dopaminergic Neurons ◽

Cell Loss ◽

Alpha Synuclein ◽

Mice Model ◽

Dopaminergic Cell ◽

The Brain

Abstract Parkinson’s disease (PD) is known as the second most common neurodegenerative disease, which is caused by destruction of dopaminergic neurons in the substantia nigra (SN) of the brain; however, the reason for the death of dopaminergic neurons remains unclear. An increase in α-synuclein (α-syn) is considered an important factor in the pathogenesis of PD. In the current study, we investigated the association between PD and serine/arginine-rich protein specific kinase 3 (Srpk3) in MPTP-induced parkinsonism mice model and in SH-SY5Y cells treated with MPP+. Srpk3 expression was significantly downregulated, while tyrosine hydroxylase (TH) decreased and α-synuclein (α-syn) increased after 4 weeks of MPTP intoxication treatment. Dopaminergic cell reduction and α-syn increase were demonstrated by inhibiting Srpk3 expression by siRNA in SH-SY5Y cells. Moreover, a decrease in Srpk3 expression upon siRNA treatment promoted dopaminergic cell reduction and α-syn increase in SH-SY5Y cells treated with MPP+. These results suggest that the decrease in Srpk3 expression due to Srpk3 siRNA caused both a decrease in TH and an increase in α-syn. This raises new possibilities for studying how Srpk3 controls dopaminergic cells and α-syn expression, which may be related to the pathogenesis of PD. Our results provide an avenue for understanding the role of Srpk3 during dopaminergic cell loss and α-syn increase in the SN. Furthermore, this study could support a therapeutic possibility for PD in that the maintenance of Srpk3 expression inhibited dopaminergic cell reduction.

Download Full-text

Hyposmia as a marker of (non-)motor disease severity in Parkinson’s disease

Journal of Neural Transmission ◽

10.1007/s00702-019-02074-0 ◽

2019 ◽

Vol 126 (11) ◽

pp. 1471-1478 ◽

Cited By ~ 7

Author(s):

Dareia S. Roos ◽

Jos W. R. Twisk ◽

Pieter G. H. M. Raijmakers ◽

Richard L. Doty ◽

Henk W. Berendse

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Sleep Disturbances ◽

Psychiatric Symptoms ◽

Cell Loss ◽

Motor Symptoms ◽

Dopaminergic Cell ◽

Dat Spect ◽

Spect Scan ◽

Non Motor Symptoms

Abstract The aim of this study was to evaluate the relationship of hyposmia in Parkinson’s disease (PD) with other motor and non-motor symptoms and with the degree of nigrostriatal dopaminergic cell loss. A total of 295 patients with a diagnosis of PD were included. Olfactory function was measured using the University of Pennsylvania Smell Identification Test (UPSIT). Motor symptoms were rated using the Unified Parkinson’s Disease Rating Scale motor subscale (UPDRS III). To evaluate other non-motor symptoms, we used the Mini-Mental State Examination (MMSE) as a measure of global cognitive function and validated questionnaires to assess sleep disturbances, psychiatric symptoms, and autonomic dysfunction. A linear regression model was used to calculate correlation coefficients between UPSIT score and motor and non-motor variables [for psychiatric symptoms a Poisson regression was performed]. In a subgroup of patients (n = 155) with a dopamine transporter (DaT) SPECT scan, a similar statistical analysis was performed, now including striatal DaT binding. In the regression models with correction for age, sex, disease duration, and multiple testing, all motor and non-motor symptoms were associated with UPSIT scores. In the subgroup of patients with a DaT-SPECT scan, there was a strong association between olfactory test scores and DaT binding in both putamen and caudate nucleus. Hyposmia in PD is associated with various motor and non-motor symptoms, like cognition, depression, anxiety, autonomic dysfunction and sleep disturbances, and with the degree of nigrostriatal dopaminergic cell loss. This finding adds further confirmation that hyposmia holds significant promise as a marker of disease progression.

Download Full-text

MMP13 Expression Is Increased Following Mutant α-Synuclein Exposure and Promotes Inflammatory Responses in Microglia

Frontiers in Neuroscience ◽

10.3389/fnins.2020.585544 ◽

2020 ◽

Vol 14 ◽

Author(s):

Kathryn Sánchez ◽

Kathleen Maguire-Zeiss

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Nuclear Translocation ◽

Inflammatory Responses ◽

Receptor Activation ◽

Proinflammatory Response ◽

Molecular Pattern ◽

Lewy Body Pathology ◽

Acid Protein

α-Synuclein is a 140-amino acid protein that readily misfolds and is associated with the Lewy body pathology found in sporadic and genetic forms of Parkinson's disease. We and others have shown that wild-type α-synuclein is a damage-associated molecular pattern that directly elicits a proinflammatory response in microglia through toll-like receptor activation. Here we investigated the direct effect of oligomeric mutant α-synuclein (A53T) on microglia morphology and activation. We found that misfolded A53T increased quantitative measures of amoeboid cell morphology, NFκB nuclear translocation and the expression of prototypical proinflammatory molecules. We also demonstrated that A53T increased expression of MMP13, a matrix metalloproteinase that remodels the extracellular matrix. To better understand the role of MMP13 in synucleinopathies, we further characterized the role of MMP13 in microglial signaling. We showed exposure of microglia to MMP13 induced a change in morphology and promoted the release of TNFα and MMP9. Notably, IL1β was not released indicating that the pathway involved in MMP13 activation of microglia may be different than the A53T pathway. Lastly, MMP13 increased the expression of CD68 suggesting that the lysosomal pathway might be altered by this MMP. Taken together this study shows that mutant α-synuclein directly induces a proinflammatory phenotype in microglia, which includes the expression of MMP13. In turn, MMP13 directly alters microglia supporting the need for multi-target therapies to treat Parkinson's disease patients.

Download Full-text