scholarly journals Structure of PINK1 and mechanisms of Parkinson's disease-associated mutations

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Atul Kumar ◽  
Jevgenia Tamjar ◽  
Andrew D Waddell ◽  
Helen I Woodroof ◽  
Olawale G Raimi ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Autosomal Recessive ◽  
Kinase Domain ◽  
Loss Of Function ◽  
Structural Element ◽  
Human Kinase ◽  
Distal Loop ◽  
Small Molecule Modulators ◽  
Early Onset Parkinson’S Disease

Mutations in the human kinase PINK1 (hPINK1) are associated with autosomal recessive early-onset Parkinson's disease (PD). hPINK1 activates Parkin E3 ligase activity, involving phosphorylation of ubiquitin and the Parkin ubiquitin-like (Ubl) domain via as yet poorly understood mechanisms. hPINK1 is unusual amongst kinases due to the presence of three loop insertions of unknown function. We report the structure of Tribolium castaneum PINK1 (TcPINK1), revealing several unique extensions to the canonical protein kinase fold. The third insertion, together with autophosphorylation at residue Ser205, contributes to formation of a bowl-shaped binding site for ubiquitin. We also define a novel structural element within the second insertion that is held together by a distal loop that is critical for TcPINK1 activity. The structure of TcPINK1 explains how PD-linked mutations that lie within the kinase domain result in hPINK1 loss-of-function and provides a platform for the exploration of small molecule modulators of hPINK1.

scholarly journals Parkin is recruited selectively to impaired mitochondria and promotes their autophagy

2008 ◽  
Vol 183 (5) ◽  
pp. 795-803 ◽  
Author(s):  
Derek Narendra ◽  
Atsushi Tanaka ◽  
Der-Fen Suen ◽  
Richard J. Youle
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mammalian Cells ◽  
Loss Of Function ◽  
Gene Coding ◽  
Selective Elimination ◽  
Mitochondrial Toxins ◽  
Early Onset Parkinson’S Disease ◽  
Increased Susceptibility

Loss-of-function mutations in Park2, the gene coding for the ubiquitin ligase Parkin, are a significant cause of early onset Parkinson's disease. Although the role of Parkin in neuron maintenance is unknown, recent work has linked Parkin to the regulation of mitochondria. Its loss is associated with swollen mitochondria and muscle degeneration in Drosophila melanogaster, as well as mitochondrial dysfunction and increased susceptibility to mitochondrial toxins in other species. Here, we show that Parkin is selectively recruited to dysfunctional mitochondria with low membrane potential in mammalian cells. After recruitment, Parkin mediates the engulfment of mitochondria by autophagosomes and the selective elimination of impaired mitochondria. These results show that Parkin promotes autophagy of damaged mitochondria and implicate a failure to eliminate dysfunctional mitochondria in the pathogenesis of Parkinson's disease.

scholarly journals Comprehensive assessment of PINK1 variants in Parkinson’s disease

2020 ◽  
Author(s):  
Lynne Krohn ◽  
Francis P. Grenn ◽  
Mary B. Makarious ◽  
Jonggeol Jeffrey Kim ◽  
Sara Bandres-Ciga ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Risk Factor ◽  
Autosomal Recessive ◽  
Disease Susceptibility ◽  
Large Datasets ◽  
The Past ◽  
Increased Risk ◽  
Early Onset Parkinson’S Disease

AbstractMultiple genes have been associated with monogenic Parkinson’s disease and Parkinsonism syndromes. Mutations in PINK1 (PARK6) have been shown to result in autosomal recessive early onset Parkinson’s disease. In the past decade, several studies have suggested that carrying a single heterozygous PINK1 mutation is associated with increased risk for Parkinson’s disease. Here we comprehensively assess the role of PINK1 variants in Parkinson’s disease susceptibility using several large datasets totalling 376,558 individuals including: 13,708 Parkinson’s disease cases and 362,850 controls. After combining these data, we did not find evidence to support a role for heterozygous PINK1 mutations as a risk factor for Parkinson’s disease.

scholarly journals Parkin beyond Parkinson’s Disease—A Functional Meaning of Parkin Downregulation in TDP-43 Proteinopathies

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3389
Author(s):  
Katarzyna Gaweda-Walerych ◽  
Emilia Jadwiga Sitek ◽  
Ewa Narożańska ◽  
Emanuele Buratti
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Amyotrophic Lateral Sclerosis ◽  
Frontotemporal Lobar Degeneration ◽  
Loss Of Function ◽  
Disease Phenotypes ◽  
Selective Elimination ◽  
Functional Implications ◽  
Lateral Sclerosis ◽  
Early Onset Parkinson’S Disease

Parkin and PINK1 are key regulators of mitophagy, an autophagic pathway for selective elimination of dysfunctional mitochondria. To this date, parkin depletion has been associated with recessive early onset Parkinson’s disease (PD) caused by loss-of-function mutations in the PARK2 gene, while, in sporadic PD, the activity and abundance of this protein can be compromised by stress-related modifications. Intriguingly, research in recent years has shown that parkin depletion is not limited to PD but is also observed in other neurodegenerative diseases—especially those characterized by TDP-43 proteinopathies, such as amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Here, we discuss the evidence of parkin downregulation in these disease phenotypes, its emerging connections with TDP-43, and its possible functional implications.

„Early Onset Parkinson's Disease“: Korrelation zwischen Alter bei Krankheitsbeginn und Verlauf?

2005 ◽  
Vol 32 (S 1) ◽  
Author(s):  
A Janzen ◽  
B Winner ◽  
M Lange ◽  
Z Kohl ◽  
K Pfeifer ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Early Onset ◽  
Early Onset Parkinson’S Disease
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