scholarly journals Deubiquitinase USP29 Governs MYBBP1A in the Brains of Parkinson’s Disease Patients

2019 ◽  
Vol 9 (1) ◽  
pp. 52 ◽  
Author(s):  
Areum Jo ◽  
Yunjong Lee ◽  
Chi-Hu Park ◽  
Joo-Ho Shin
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Transgenic Mice ◽  
Neuronal Death ◽  
Binding Protein ◽  
Post Translational Modification ◽  
Ventral Midbrain ◽  
Postmortem Brains

The inactivation of parkin by mutation or post-translational modification contributes to dopaminergic neuronal death in Parkinson’s disease (PD). The substrates of parkin, FBP1 and AIMP2, are accumulated in the postmortem brains of PD patients, and it was recently suggested that these parkin substrates transcriptionally activate deubiquitinase USP29. Herein, we newly identified 160 kDa myb-binding protein (MYBBP1A) as a novel substrate of USP29. Knockdown of parkin increased the level of AIMP2, leading to ultimately USP29 and MYBBP1A accumulation in SH-SY5Y cells. Notably, MYBBP1A was downregulated in the ventral midbrain (VM) of Aimp2 knockdown mice, whereas the upregulation of MYBBP1A was observed in the VM of inducible AIMP2 transgenic mice, as well as in the substantia nigra of sporadic PD patients. These results suggest that AIMP2 upregulates USP29 and MYBBP1A in the absence of parkin activity, contributing to PD pathogenesis.

PARIS farnesylation prevents neurodegeneration in models of Parkinson’s disease

2021 ◽  
Vol 13 (604) ◽  
pp. eaax8891
Author(s):  
Areum Jo ◽  
Yunjong Lee ◽  
Tae-In Kam ◽  
Sung-Ung Kang ◽  
Stewart Neifert ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Transgenic Mice ◽  
Neuronal Loss ◽  
Peroxisome Proliferator ◽  
Behavioral Deficits ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ventral Midbrain ◽  
Dopaminergic Neuronal Loss

Accumulation of the parkin-interacting substrate (PARIS; ZNF746), due to inactivation of parkin, contributes to Parkinson’s disease (PD) through repression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α; PPARGC1A) activity. Here, we identify farnesol as an inhibitor of PARIS. Farnesol promoted the farnesylation of PARIS, preventing its repression of PGC-1α via decreasing PARIS occupancy on the PPARGC1A promoter. Farnesol prevented dopaminergic neuronal loss and behavioral deficits via farnesylation of PARIS in PARIS transgenic mice, ventral midbrain transduction of AAV-PARIS, adult conditional parkin KO mice, and the α-synuclein preformed fibril model of sporadic PD. PARIS farnesylation is decreased in the substantia nigra of patients with PD, suggesting that reduced farnesylation of PARIS may play a role in PD. Thus, farnesol may be beneficial in the treatment of PD by enhancing the farnesylation of PARIS and restoring PGC-1α activity.

Lack of Association of Locus Coeruleus Pathology with Orthostatic Hypotension in Parkinson’s Disease

2020 ◽  
pp. 1-5
Author(s):  
Qiang Tong ◽  
Liam Chen
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Orthostatic Hypotension ◽  
Locus Coeruleus ◽  
The Elderly ◽  
Motor Symptom ◽  
Postmortem Brains ◽  
The Relationship ◽  
The Brain

Orthostatic hypotension (OH) is a common non-motor symptom in Parkinson’s disease (PD) and is linked with increased mortality risk among the elderly. Although the locus coeruleus (LC) is the major source of noradrenaline (NA) modulation in the brain, its role in the pathogenesis of OH in PD remains largely elusive. Here we examined 44 well characterized postmortem brains of PD patients and available clinical data to explore the relationship between OH and LC pathology in PD. Our results failed to indicate that the LC pathology as well as the substantia nigra pathology were robustly associated with the presence of OH in PD patients, suggesting targeting LC norepinephrinergic system alone may not be sufficient to treat OH in PD.

scholarly journals Tau Knockout and α-Synuclein A53T Synergy Modulated Parvalbumin-Positive Neurons Degeneration Staging in Substantia Nigra Pars Reticulata of Parkinson’s Disease-Liked Model

2022 ◽  
Vol 13 ◽  
Author(s):  
Meige Zheng ◽  
Yanchang Liu ◽  
Zhaoming Xiao ◽  
Luyan Jiao ◽  
Xian Lin
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Transgenic Mice ◽  
Molecular Mechanism ◽  
The Other ◽  
Substantia Nigra Pars Reticulata ◽  
Transitional Stage ◽  
Mice Model ◽  
End Stage

The loss of parvalbumin-positive (PV+) neurons in the substantia nigra pars reticulata (SNR) was observed in patients with end-stage Parkinson’s disease (PD) and our previously constructed old-aged Pitx3-A53Tα-Syn × Tau–/– triple transgenic mice model of PD. The aim of this study was to examine the progress of PV+ neurons loss. We demonstrated that, as compared with non-transgenic (nTg) mice, the accumulation of α-synuclein in the SNR of aged Pitx3-A53Tα-Syn × Tau–/– mice was increased obviously, which was accompanied by the considerable degeneration of PV+ neurons and the massive generation of apoptotic NeuN+TUNEL+ co-staining neurons. Interestingly, PV was not costained with TUNEL, a marker of apoptosis. PV+ neurons in the SNR may undergo a transitional stage from decreased expression of PV to increased expression of NeuN and then to TUNEL expression. In addition, the degeneration of PV+ neurons and the expression of NeuN were rarely observed in the SNR of nTg and the other triple transgenic mice. Hence, we propose that Tau knockout and α-syn A53T synergy modulate PV+ neurons degeneration staging in the SNR of aged PD-liked mice model, and NeuN may be suited for an indicator that suggests degeneration of SNR PV+ neurons. However, the molecular mechanism needs to be further investigated.

scholarly journals Blood-Derived α-Synuclein Aggregated in the Substantia Nigra of Parabiotic Mice

Biomolecules ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 1287
Author(s):  
Xizhen Ma ◽  
Leilei Chen ◽  
Ning Song ◽  
Le Qu ◽  
Jun Wang ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Transgenic Mice ◽  
Direct Evidence ◽  
Short Period ◽  
Significant Change ◽  
The Brain

As a pathological biomarker of Parkinson’s disease, α-synuclein is thought to be a prion-like protein, but evidence for the transmission of α-synuclein from blood to the brain is unclear. The goals of this study were to determine whether blood-derived α-synuclein could enter the brains of mice and whether α-synuclein in the brain could be cleared by parabiosis. Heterochronic parabiosis was performed on SNCAA53T transgenic mice (A53T mice) and wildtype mice. The levels of human α-synuclein in the blood and substantia nigra of wildtype mice were significantly increased after 4-month parabiosis with A53T mice. Moreover, the expression of α-synuclein filament, but not of total α-synuclein, was significantly increased in the substantia nigra of wildtype mice that were paired with A53T mice. However, the levels of human α-synuclein displayed no significant change in the serum, blood, or substantia nigra of A53T mice. These results provide direct evidence that pathological α-synuclein can be transmitted from blood to the brain in the heterochronic parabiosis system; however, it appears to be difficult to clear it from the brain in a short period of time.

scholarly journals Celastrol Inhibits Dopaminergic Neuronal Death of Parkinson’s Disease through Activating Mitophagy

Antioxidants ◽  
2019 ◽  
Vol 9 (1) ◽  
pp. 37 ◽  
Author(s):  
Ming-Wei Lin ◽  
Chi Chien Lin ◽  
Yi-Hung Chen ◽  
Han-Bin Yang ◽  
Shih-Ya Hung
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Neuronal Death ◽  
Neuronal Apoptosis ◽  
Cell Model ◽  
Protein Accumulation ◽  
Motor Symptoms ◽  
Abnormal Protein ◽  
Mitochondrial Membrane Depolarization

Parkinson’s disease (PD) is a neurodegenerative disease, which is associated with mitochondrial dysfunction and abnormal protein accumulation. No treatment can stop or slow PD. Autophagy inhibits neuronal death by removing damaged mitochondria and abnormal protein aggregations. Celastrol is a triterpene with antioxidant and anti-inflammatory effects. Up until now, no reports have shown that celastrol improves PD motor symptoms. In this study, we used PD cell and mouse models to evaluate the therapeutic efficacy and mechanism of celastrol. In the substantia nigra, we found lower levels of autophagic activity in patients with sporadic PD as compared to healthy controls. In neurons, celastrol enhances autophagy, autophagosome biogenesis (Beclin 1↑, Ambra1↑, Vps34↑, Atg7↑, Atg12↑, and LC3-II↑), and mitophagy (PINK1↑, DJ-1↑, and LRRK2↓), and these might be associated with MPAK signaling pathways. In the PD cell model, celastrol reduces MPP+-induced dopaminergic neuronal death, mitochondrial membrane depolarization, and ATP reduction. In the PD mouse model, celastrol suppresses motor symptoms and neurodegeneration in the substantia nigra and striatum and enhances mitophagy (PINK1↑ and DJ-1↑) in the striatum. Using MPP+ to induce mitochondrial damage in neurons, we found celastrol controls mitochondrial quality by sequestering impaired mitochondria into autophagosomes for degradation. This is the first report to show that celastrol exerts neuroprotection in PD by activating mitophagy to degrade impaired mitochondria and further inhibit dopaminergic neuronal apoptosis. Celastrol may help to prevent and treat PD.

scholarly journals Neuronal hemoglobin induces α-synuclein cleavage and loss of dopaminergic neurons

2021 ◽  
Author(s):  
Chiara Santulli ◽  
Carlotta Bon ◽  
Elena De Cecco ◽  
Marta Codrich ◽  
Joanna Narkiewicz ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Dopaminergic Neurons ◽  
Spatial Working Memory ◽  
Dopamine Neurons ◽  
Substantia Nigra Pars Compacta ◽  
Major Protein ◽  
Post Translational Modification ◽  
Over Expression

Backgroud α-synuclein, a protein involved in the pathogenesis of several neurodegenerative disorders, is subjected to several post-translational modifications. Among them, C-terminal truncation seems to increase its aggregation propensity in vitro. Hemoglobin is the major protein in erythrocytes to carries oxygen and recently is found to be expressed in dopaminergic neurons and to be involved in the pathogenesis of neurodegenerative diseases such as Parkinson's disease. Methods To assess the role of hemoglobin in α-synuclein post-translational modification and in dopamine cells physiology, we over-expressed α and β-chains of Hb in iMN9D dopamine cells to evaluate its effect on α-synuclein truncation. Using an AAV9 we expressed α and β-chains of hemoglobin in dopamine neurons of Substantia Nigra pars compacta and evaluate its effect on α-synuclein post-translational modification, dopamine neurons survivals and behavioural outcome. Results The over-expression of α and β-chains of hemoglobin in iMN9D dopamine cells increased C-terminal truncation of α-synuclein when cells were treated with α-synuclein preformed fibrils. This cleavage was led at least in part by Calpain protease. Hemoglobin over-expression in Substantia Nigra pars compacta induced a similar pattern of α-synuclein truncation and a decrease in tyrosine hydroxylase expression, unveiling a decrease of dopamine neurons of about 50%. This dopamine cells loss led to a mild motor impairment and a deficit in recognition and spatial working memory. Conclusion Our study reveals a novel role for hemoglobin in α-synuclein post-translational modification and in dopamine neurons homeostasis suggesting neuronal hemoglobin is an important modifier in synucleinopathies such as Parkinson's disease.

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