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 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.

scholarly journals Loss of UCHL1 rescues the defects related to Parkinson’s disease by suppressing glycolysis

2021 ◽  
Vol 7 (28) ◽  
pp. eabg4574
Author(s):  
Su Jin Ham ◽  
Daewon Lee ◽  
Wen Jun Xu ◽  
Eunjoo Cho ◽  
Sekyu Choi ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Protein Kinase ◽  
Pyruvate Kinase ◽  
Mammalian Cells ◽  
Loss Of Function ◽  
Tripartite Motif ◽  
Carboxyl Terminal ◽  
Amp Activated Protein Kinase

The role of ubiquitin carboxyl-terminal hydrolase L1 (UCHL1; also called PARK5) in the pathogenesis of Parkinson’s disease (PD) has been controversial. Here, we find that the loss of UCHL1 destabilizes pyruvate kinase (PKM) and mitigates the PD-related phenotypes induced by PTEN-induced kinase 1 (PINK1) or Parkin loss-of-function mutations in Drosophila and mammalian cells. In UCHL1 knockout cells, cellular pyruvate production and ATP levels are diminished, and the activity of AMP–activated protein kinase (AMPK) is highly induced. Consequently, the activated AMPK promotes the mitophagy mediated by Unc-51–like kinase 1 (ULK1) and FUN14 domain–containing 1 (FUNDC1), which underlies the effects of UCHL1 deficiency in rescuing PD-related defects. Furthermore, we identify tripartite motif–containing 63 (TRIM63) as a previously unknown E3 ligase of PKM and demonstrate its antagonistic interaction with UCHL1 to regulate PD-related pathologies. These results suggest that UCHL1 is an integrative factor for connecting glycolysis and PD pathology.

scholarly journals Genetic Mutations and Mitochondrial Toxins Shed New Light on the Pathogenesis of Parkinson's Disease

2011 ◽  
Vol 2011 ◽  
pp. 1-7 ◽  
Author(s):  
Shigeto Sato ◽  
Nobutaka Hattori
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mitochondrial Dysfunction ◽  
Cultured Cells ◽  
Cellular Functions ◽  
Carbonyl Cyanide ◽  
Mitochondrial Toxins ◽  
Cellular Abnormalities ◽  
Mitochondrial Uncoupler

The cellular abnormalities in Parkinson's disease (PD) include mitochondrial dysfunction and oxidative damage, which are probably induced by both genetic predisposition and environmental factors. Mitochondrial dysfunction has long been implicated in the pathogenesis of PD. The recent discovery of genes associated with the etiology of familial PD has emphasized the role of mitochondrial dysfunction in PD. The discovery and increasing knowledge of the function of PINK1 and parkin, which are associated with the mitochondria, have also enhanced the understanding of cellular functions. The PINK1-parkin pathway is associated with quality control of the mitochondria, as determined in cultured cells treated with the mitochondrial uncoupler carbonyl cyanide m-chlorophenylhydrazone (CCCP), which causes mitochondrial depolarization. To date, the use of mitochondrial toxins, for example, 1-methyl-4-phynyl-tetrahydropyridine (MPTP) and CCCP, has contributed to our understanding of PD. We review how these toxins and familial PD gene products are associated with and have enhanced our understanding of the role of mitochondrial dysfunction in PD.

scholarly journals The Role of the Dopamine β-hydroxylase Functional Polymorphism in Patients with Early-Onset Parkinson’s Disease in the Turkish Population

2021 ◽  
Vol 27 (1) ◽  
pp. 21-26
Author(s):  
Sevda Erer ◽  
Işıl Ezgi Eryılmaz ◽  
Dilara Kamer Çolak ◽  
Ünal Egeli ◽  
Gülşah Çeçener ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Early Onset ◽  
Turkish Population ◽  
Functional Polymorphism ◽  
Early Onset Parkinson’S Disease

scholarly journals Role of Cleaved PINK1 in Neuronal Development, Synaptogenesis, and Plasticity: Implications for Parkinson’s Disease

2021 ◽  
Vol 15 ◽  
Author(s):  
Smijin K. Soman ◽  
Ruben K. Dagda
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neuronal Development ◽  
Structural Integrity ◽  
Intermembrane Space ◽  
Loss Of Function ◽  
Serine Threonine Kinase ◽  
Functional Roles ◽  
Neuronal Functions

Mitochondrial dysfunction plays a significant role in the pathogenesis of Parkinson’s disease (PD). Consistent with this concept, loss of function mutations in the serine/threonine kinase- PINK1 (PTEN-induced putative kinase-1) causes autosomal recessive early onset PD. While the functional role of f-PINK1 (full-length PINK1) in clearing dysfunctional mitochondria via mitophagy is extensively documented, our understanding of specific physiological roles that the non-mitochondrial pool of PINK1 imparts in neurons is more limited. PINK1 is proteolytically processed in the intermembrane space and matrix of the mitochondria into functional cleaved products (c-PINK1) that are exported to the cytosol. While it is clear that posttranslational processing of PINK1 depends on the mitochondria’s oxidative state and structural integrity, the functional roles of c-PINK1 in modulating neuronal functions are poorly understood. Here, we review the diverse roles played by c-PINK1 in modulating various neuronal functions. Specifically, we describe the non-canonical functional roles of PINK1, including but not limited to: governing mitochondrial movement, neuronal development, neuronal survival, and neurogenesis. We have published that c-PINK1 stimulates neuronal plasticity and differentiation via the PINK1-PKA-BDNF signaling cascade. In addition, we provide insight into how mitochondrial membrane potential-dependent processing of PINK1 confers conditional retrograde signaling functions to PINK1. Further studies delineating the role of c-PINK1 in neurons would increase our understanding regarding the role played by PINK1 in PD pathogenesis.

scholarly journals Mitochondrial Serine Protease HTRA2 p.G399S in a Female with Di George Syndrome and Parkinson’s Disease

2018 ◽  
Vol 2018 ◽  
pp. 1-6 ◽  
Author(s):  
Stefano Gambardella ◽  
Rosangela Ferese ◽  
Simona Scala ◽  
Stefania Carboni ◽  
Francesca Biagioni ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Risk Factor ◽  
Sequencing Analysis ◽  
Pathogenetic Role ◽  
Number Of Patients ◽  
History Of ◽  
Early Onset Parkinson’S Disease ◽  
Di George Syndrome

Deletion at 22q11.2 responsible for Di George syndrome (DGs) is a risk factor for early-onset Parkinson’s disease (EOPD). To date, all patients reported with 22q11.2 deletions and parkinsonian features are negative for a family history of PD, and possible mutations in PD-related genes were not properly evaluated. The goal of this paper was to identify variants in PD genes that could contribute, together with 22q11.2 del, to the onset of parkinsonian features in patients affected by Di George syndrome. To this aim, sequencing analysis of 4800 genes including 17 PD-related genes was performed in a patient affected by DGs and EOPD. The analysis identified mutation p.Gly399Ser in OMI/HTRA2 (PARK13). To date, the mechanism that links DGs with parkinsonian features is poorly understood. The identification of a mutation in a PARK gene suggests that variants in PD-related genes, or in genes still not associated with PD, could contribute, together with deletion at 22q11.2, to the EOPD in patients affected by DGs. Further genetic analyses in a large number of patients are strongly required to understand this mechanism and to establish the pathogenetic role of p.Gly399Ser in OMI/HTRA2.

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.

Evaluating the Role of SNCA , LRRK2 , and GBA in Chinese Patients With Early‐Onset Parkinson's Disease

2020 ◽  
Vol 35 (11) ◽  
pp. 2046-2055 ◽  
Author(s):  
Yongping Chen ◽  
Xiaojing Gu ◽  
Ruwei Ou ◽  
Lingyu Zhang ◽  
Yanbing Hou ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Early Onset ◽  
Chinese Patients ◽  
Early Onset Parkinson’S Disease

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.

Sign in / Sign up

Export Citation Format

Share Document