scholarly journals Mitochondrial E3 Ubiquitin Ligase Parkin: Relationships with Other Causal Proteins in Familial Parkinson’s Disease and Its Substrate-Involved Mouse Experimental Models

2020 ◽  
Vol 21 (4) ◽  
pp. 1202 ◽  
Author(s):  
Satoru Torii ◽  
Shuya Kasai ◽  
Tatsushi Yoshida ◽  
Ken-ichi Yasumoto ◽  
Shigeomi Shimizu
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Ubiquitin Ligase ◽  
Transcriptional Repression ◽  
Neurodegenerative Disorder ◽  
E3 Ubiquitin Ligase ◽  
Experimental Models ◽  
Dual Function ◽  
Key Factors ◽  
Post Translational Modifications

Parkinson’s disease (PD) is a common neurodegenerative disorder. Recent identification of genes linked to familial forms of PD has revealed that post-translational modifications, such as phosphorylation and ubiquitination of proteins, are key factors in disease pathogenesis. In PD, E3 ubiquitin ligase Parkin and the serine/threonine-protein kinase PTEN-induced kinase 1 (PINK1) mediate the mitophagy pathway for mitochondrial quality control via phosphorylation and ubiquitination of their substrates. In this review, we first focus on well-characterized PINK1 phosphorylation motifs. Second, we describe our findings concerning relationships between Parkin and HtrA2/Omi, a protein involved in familial PD. Third, we describe our findings regarding inhibitory PAS (Per/Arnt/Sim) domain protein (IPAS), a member of PINK1 and Parkin substrates, involved in neurodegeneration during PD. IPAS is a dual-function protein involved in transcriptional repression of hypoxic responses and the pro-apoptotic activities.

scholarly journals The Landscape of Parkin Variants Reveals Pathogenic Mechanisms and Therapeutic Targets in Parkinson’s Disease

2018 ◽  
Author(s):  
Wei Yi ◽  
Emma J. MacDougall ◽  
Matthew Y. Tang ◽  
Andrea I. Krahn ◽  
Ziv Gan-Or ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Specific Drug ◽  
Common Cause ◽  
Naturally Occurring ◽  
Population Databases ◽  
Early Onset Parkinson’S Disease

AbstractMutations in Parkin (PARK2), which encodes an E3 ubiquitin ligase implicated in mitophagy, are the most common cause of early onset Parkinson’s Disease (PD). Hundreds of naturally occurring Parkin variants have been reported, both in PD patient and population databases. However, the effects of the majority of these variants on the function of Parkin and in PD pathogenesis remains unknown. Here we develop a framework for classification of the pathogenicity of Parkin variants based on the integration of clinical and functional evidence – including measures of mitophagy and protein stability, and predictive structural modeling – and assess 51 naturally occurring Parkin variants accordingly. Surprisingly, only a minority of Parkin variants, even among those previously associated with PD, disrupted Parkin function. Moreover, a few of these naturally occurring Parkin variants actually enhanced mitophagy. Interestingly, impaired mitophagy in several of the most common pathogenic Parkin variants could be rescued both by naturally-occurring (p.V224A) and structure-guided designer (p.W403A; p.F146A) hyperactive Parkin variants. Together, the findings provide a coherent framework to classify Parkin variants based on pathogenicity and suggest that several pathogenic Parkin variants represent promising targets to stratify patients for genotype-specific drug design.

scholarly journals The Rotenone Models Reproducing Central and Peripheral Features of Parkinson’s Disease

NeuroSci ◽  
2020 ◽  
Vol 1 (1) ◽  
pp. 1-14
Author(s):  
Ikuko Miyazaki ◽  
Masato Asanuma
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Nervous System ◽  
Peripheral Nervous System ◽  
Neurodegenerative Disorder ◽  
Rem Sleep Behavior Disorder ◽  
Experimental Models ◽  
Motor Symptoms ◽  
Sleep Behavior ◽  
Disease Modifying Drugs

Parkinson’s disease (PD) is a complex, multi-system, neurodegenerative disorder; PD patients exhibit motor symptoms (such as akinesia/bradykinesia, tremor, rigidity, and postural instability) due to a loss of nigrostriatal dopaminergic neurons, and non-motor symptoms such as hyposmia, autonomic disturbance, depression, and REM sleep behavior disorder (RBD), which precedes motor symptoms. Pathologically, α-synuclein deposition is observed in the central and peripheral nervous system of sporadic PD patients. To clarify the mechanism of neurodegeneration in PD and to develop treatment to slow or stop PD progression, there is a great need for experimental models which reproduce neurological features of PD. Animal models exposed to rotenone, a commonly used pesticide, have received most attention since Greenamyre and his colleagues reported that chronic exposure to rotenone could reproduce the anatomical, neurochemical, behavioral, and neuropathological features of PD. In addition, recent studies demonstrated that rotenone induced neuropathological change not only in the central nervous system but also in the peripheral nervous system in animals. In this article, we review rotenone models especially focused on reproducibility of central and peripheral multiple features of PD. This review also highlights utility of rotenone models for investigation of PD pathogenesis and development of disease-modifying drugs for PD in future.

The FBXO7 homologue nutcracker and binding partner PI31 in Drosophila melanogaster models of Parkinson’s disease

Genome ◽  
2017 ◽  
Vol 60 (1) ◽  
pp. 46-54 ◽  
Author(s):  
Eric M. Merzetti ◽  
Lindsay A. Dolomount ◽  
Brian E. Staveley
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Drosophila Melanogaster ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Severe Form ◽  
Altered Expression ◽  
Binding Partner ◽  
Locomotor Control ◽  
Dependent Model

Parkinsonian-pyramidal syndrome (PPS) is an early onset form of Parkinson’s disease (PD) that shows degeneration of the extrapyramidal region of the brain to result in a severe form of PD. The toxic protein build-up has been implicated in the onset of PPS. Protein removal is mediated by an intracellular proteasome complex: an E3 ubiquitin ligase, the targeting component, is essential for function. FBXO7 encodes the F-box component of the SCF E3 ubiquitin ligase linked to familial forms of PPS. The Drosophila melanogaster homologue nutcracker (ntc) and a binding partner, PI31, have been shown to be active in proteasome function. We show that altered expression of either ntc or PI31 in dopaminergic neurons leads to a decrease in longevity and locomotor ability, phenotypes both associated with models of PD. Furthermore, expression of ntc-RNAi in an established α-synuclein-dependent model of PD rescues the phenotypes of diminished longevity and locomotor control.

scholarly journals TRIM9, a novel brain-specific E3 ubiquitin ligase, is repressed in the brain of Parkinson's disease and dementia with Lewy bodies

2010 ◽  
Vol 38 (2) ◽  
pp. 210-218 ◽  
Author(s):  
Kunikazu Tanji ◽  
Tetsu Kamitani ◽  
Fumiaki Mori ◽  
Akiyoshi Kakita ◽  
Hitoshi Takahashi ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Ubiquitin Ligase ◽  
Dementia With Lewy Bodies ◽  
E3 Ubiquitin Ligase ◽  
Lewy Bodies ◽  
The Brain

scholarly journals Parkinson’s Disease-Related Genes and Lipid Alteration

2021 ◽  
Vol 22 (14) ◽  
pp. 7630
Author(s):  
Milena Fais ◽  
Antonio Dore ◽  
Manuela Galioto ◽  
Grazia Galleri ◽  
Claudia Crosio ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Molecular Mechanisms ◽  
Neurodegenerative Disorder ◽  
Clinical Manifestations ◽  
Alpha Synuclein ◽  
Experimental Models ◽  
Protein Clearance ◽  
Genetic And Environmental Factors

Parkinson’s disease (PD) is a complex and progressive neurodegenerative disorder with a prevalence of approximately 0.5–1% among those aged 65–70 years. Although most of its clinical manifestations are due to a loss of dopaminergic neurons, the PD etiology is largely unknown. PD is caused by a combination of genetic and environmental factors, and the exact interplay between genes and the environment is still debated. Several biological processes have been implicated in PD, including mitochondrial or lysosomal dysfunctions, alteration in protein clearance, and neuroinflammation, but a common molecular mechanism connecting the different cellular alterations remains incompletely understood. Accumulating evidence underlines a significant role of lipids in the pathological pathways leading to PD. Beside the well-described lipid alteration in idiopathic PD, this review summarizes the several lipid alterations observed in experimental models expressing PD-related genes and suggests a possible scenario in relationship to the molecular mechanisms of neuronal toxicity. PD could be considered a lipid-induced proteinopathy, where alteration in lipid composition or metabolism could induce protein alteration—for instance, alpha-synuclein accumulation—and finally neuronal death.

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