scholarly journals The role of adenosine monophosphate-activated protein kinase in neurodegeneration in Parkinson's disease

2019 ◽  
Vol 70 (4) ◽  
pp. 13-20
Author(s):  
Maja Jovanović-Tucović ◽  
Ivanka Marković
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Protein Kinase ◽  
Adenosine Monophosphate

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.

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