Parkinson's Disease: Assays for the Ubiquitin Ligase Activity of Neural Parkin

ABSTRACTSomatic mutations that perturb Parkin ubiquitin ligase activity and the misregulation of iron homeostasis have both been linked to Parkinson’s disease. Lactotransferrin is a member of the transferrin iron binding proteins that regulate iron homeostasis and increased levels of Lactotransferrin and its receptor have been observed in neurodegenerative disorders like Parkinson’s disease. Here, we report that Parkin binds to Lactotransferrin and ubiquitylates it to regulate iron homeostasis.

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Interaction between Parkin and α-Synuclein in PARK2-Mediated Parkinson’s Disease

Cells ◽

10.3390/cells10020283 ◽

2021 ◽

Vol 10 (2) ◽

pp. 283

Author(s):

Daniel Aghaie Madsen ◽

Sissel Ida Schmidt ◽

Morten Blaabjerg ◽

Morten Meyer

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Ubiquitin Ligase ◽

Current Knowledge ◽

Lewy Bodies ◽

Ubiquitin Proteasome System ◽

Loss Of Function ◽

Functional Interaction ◽

Future Studies ◽

Ubiquitin Proteasome

Parkin and α-synuclein are two key proteins involved in the pathophysiology of Parkinson’s disease (PD). Neurotoxic alterations of α-synuclein that lead to the formation of toxic oligomers and fibrils contribute to PD through synaptic dysfunction, mitochondrial impairment, defective endoplasmic reticulum and Golgi function, and nuclear dysfunction. In half of the cases, the recessively inherited early-onset PD is caused by loss of function mutations in the PARK2 gene that encodes the E3-ubiquitin ligase, parkin. Parkin is involved in the clearance of misfolded and aggregated proteins by the ubiquitin-proteasome system and regulates mitophagy and mitochondrial biogenesis. PARK2-related PD is generally thought not to be associated with Lewy body formation although it is a neuropathological hallmark of PD. In this review article, we provide an overview of post-mortem neuropathological examinations of PARK2 patients and present the current knowledge of a functional interaction between parkin and α-synuclein in the regulation of protein aggregates including Lewy bodies. Furthermore, we describe prevailing hypotheses about the formation of intracellular micro-aggregates (synuclein inclusions) that might be more likely than Lewy bodies to occur in PARK2-related PD. This information may inform future studies aiming to unveil primary signaling processes involved in PD and related neurodegenerative disorders.

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

10.1101/445551 ◽

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.

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OR13,6 Regulation of IGF-I receptor signaling and the CUL7 ubiquitin ligase by the Parkinson's Disease protein GIGYF2

Growth Hormone & IGF Research ◽

10.1016/s1096-6374(08)70085-6 ◽

2008 ◽

Vol 18 ◽

pp. S26

Author(s):

W.G. Tsiaras ◽

B. Giovannone ◽

G. Karashchuk ◽

R. Smith

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Ubiquitin Ligase ◽

Receptor Signaling ◽

Igf I ◽

Disease Protein

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

Genome ◽

10.1139/gen-2016-0087 ◽

2017 ◽

Vol 60 (1) ◽

pp. 46-54 ◽

Cited By ~ 5

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.

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Disease-causing mutations in Parkin impair mitochondrial ubiquitination, aggregation, and HDAC6-dependent mitophagy

The Journal of Cell Biology ◽

10.1083/jcb.201001039 ◽

2010 ◽

Vol 189 (4) ◽

pp. 671-679 ◽

Cited By ~ 344

Author(s):

Joo-Yong Lee ◽

Yoshito Nagano ◽

J. Paul Taylor ◽

Kah Leong Lim ◽

Tso-Pang Yao

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Ubiquitin Ligase ◽

Protein Aggregate ◽

Selective Autophagy ◽

Ubiquitin Binding ◽

Microtubule Motor ◽

Mechanistic Basis ◽

Dependent Transport ◽

Familial Parkinson’S Disease

Mutations in parkin, a ubiquitin ligase, cause early-onset familial Parkinson's disease (AR-JP). How parkin suppresses Parkinsonism remains unknown. Parkin was recently shown to promote the clearance of impaired mitochondria by autophagy, termed mitophagy. Here, we show that parkin promotes mitophagy by catalyzing mitochondrial ubiquitination, which in turn recruits ubiquitin-binding autophagic components, HDAC6 and p62, leading to mitochondrial clearance. During the process, juxtanuclear mitochondrial aggregates resembling a protein aggregate-induced aggresome are formed. The formation of these “mito-aggresome” structures requires microtubule motor-dependent transport and is essential for efficient mitophagy. Importantly, we show that AR-JP–causing parkin mutations are defective in supporting mitophagy due to distinct defects at recognition, transportation, or ubiquitination of impaired mitochondria, thereby implicating mitophagy defects in the development of Parkinsonism. Our results show that impaired mitochondria and protein aggregates are processed by common ubiquitin-selective autophagy machinery connected to the aggresomal pathway, thus identifying a mechanistic basis for the prevalence of these toxic entities in Parkinson's disease.

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