scholarly journals Role of Rho-Associated Protein Kinase Inhibition As Therapeutic Strategy for Parkinson’s Disease: Dopaminergic Survival and Enhanced Mitophagy

Cureus ◽  
2021 ◽  
Author(s):  
Huma Quadir ◽  
Knkush Hakobyan ◽  
Mrunanjali Gaddam ◽  
Ugochi Ojinnaka ◽  
Zubayer Ahmed ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Protein Kinase ◽  
Therapeutic Strategy ◽  
Kinase Inhibition ◽  
Protein Kinase Inhibition

scholarly journals Role of 14-3-3-Mediated p38 Mitogen-Activated Protein Kinase Inhibition in Cardiac Myocyte Survival

2003 ◽  
Vol 93 (11) ◽  
pp. 1026-1028 ◽  
Author(s):  
Shaosong Zhang ◽  
Jie Ren ◽  
Cindy E. Zhang ◽  
Ilya Treskov ◽  
Yibin Wang ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Cardiac Myocyte ◽  
Mitogen Activated Protein Kinase ◽  
Kinase Inhibition ◽  
Protein Kinase Inhibition ◽  
Mitogen Activated Protein

scholarly journals Neuron-autonomous susceptibility to induced synuclein aggregation is exacerbated by endogenous Lrrk2 mutations and ameliorated by Lrrk2 genetic knock-out

2020 ◽  
Vol 2 (1) ◽  
Author(s):  
Sarah MacIsaac ◽  
Thaiany Quevedo Melo ◽  
Yuting Zhang ◽  
Mattia Volta ◽  
Matthew J Farrer ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Therapeutic Strategy ◽  
Germ Line ◽  
Lewy Bodies ◽  
Neuronal Cultures ◽  
Leucine Rich Repeat ◽  
Kinase Inhibition ◽  
Knock Out

Abstract Neuronal aggregates containing α-synuclein are a pathological hallmark of several degenerative diseases; including Parkinson’s disease, Parkinson’s disease with dementia and dementia with Lewy bodies. Understanding the process of α-synuclein aggregation, and discovering means of preventing it, may help guide therapeutic strategy and drug design. Recent advances provide tools to induce α-synuclein aggregation in neuronal cultures. Application of exogenous pre-formed fibrillar α-synuclein induces pathological phosphorylation and accumulation of endogenous α-synuclein, typical of that seen in disease. Genomic variability and mutations in α-synuclein and leucine-rich repeat kinase 2 proteins are the major genetic risk factors for Parkinson’s disease. Reports demonstrate fibril-induced α-synuclein aggregation is increased in cells from leucine-rich repeat kinase 2 pathogenic mutant (G2019S) overexpressing mice, and variously decreased by leucine-rich repeat kinase 2 inhibitors. Elsewhere in vivo antisense knock-down of leucine-rich repeat kinase 2 protein has been shown to protect mice from fibril-induced α-synuclein aggregation, whereas kinase inhibition did not. To help bring clarity to this issue, we took a purely genetic approach in a standardized neuron-enriched culture, lacking glia. We compared fibril treatment of leucine-rich repeat kinase 2 germ-line knock-out, and G2019S germ-line knock-in, mouse cortical neuron cultures with those from littermates. We found leucine-rich repeat kinase 2 knock-out neurons are resistant to α-synuclein aggregation, which predominantly forms within axons, and may cause axonal fragmentation. Conversely, leucine-rich repeat kinase 2 knock-in neurons are more vulnerable to fibril-induced α-synuclein accumulation. Protection and resistance correlated with basal increases in a lysosome marker in knock-out, and an autophagy marker in knock-in cultures. The data add to a growing number of studies that argue leucine-rich repeat kinase 2 silencing, and potentially kinase inhibition, may be a useful therapeutic strategy against synucleinopathy.

scholarly journals Role of the Cytoskeleton in Mediating cAMP-dependent Protein Kinase Inhibition of the Epithelial Na+/H+Exchanger NHE3

2001 ◽  
Vol 276 (44) ◽  
pp. 40761-40768 ◽  
Author(s):  
Katalin Szászi ◽  
Kazuyoshi Kurashima ◽  
Kozo Kaibuchi ◽  
Sergio Grinstein ◽  
John Orlowski
Keyword(s):  
Protein Kinase ◽  
Dependent Protein Kinase ◽  
Kinase Inhibition ◽  
Camp Dependent Protein Kinase ◽  
Protein Kinase Inhibition ◽  
Dependent Protein

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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