Proteasome and mitochondrial dynamics
Principal Investigator:
Krisztina Tar, Ph.D, assistant professor
Current lab members:
Abdennour Douida, PhD student
Azzam Aladdin, PhD student
Marvi Ghani. PhD student
Ábel Szalma, BSc student
Yi Chun Kiki Chen, MD student
Peleg Zohar, MD student
Laith Al Arab, MD student
Current projects:
Cross-talk between proteasomes and mitochondria in different models of the neurodegenerative Huntington's disease.
The role of the proteasome activator PA200 in health and disease.
Posttranslational modifications of the mitochondrial fission protein dynamin-related protein 1 (Drp1) and their role in mitochondrial dynamics.
Whole transcriptomic analysis following stable depletion of Drp1 in neuroblastoma cells.
Summary of research:
Huntington’s disease (HD) is a progressive, fatal neurodegenerative disorder caused by the extended poliQ repeat in huntingtin protein leading to protein aggregation, mitochondrial malfunction and cell death. The role of mitochondrial homeostasis, proteasome dysfunction in HD are intensively studied fields but despite the efforts still there is no clear hypothesis about their role in HD. Our aim is to study the role of the proteasome activator PA200 in the up-cleaning of the mutant huntingtin (mHtt) based aggregates which process probably influenced by the regulated degradation of the mitochondrial fission protein Drp1 and Drp1-mHtt interaction. Drp1 turnover is mediated by PA200-proteasomes and is required for normal mitochondrial homeostasis providing cytoprotection under conditions that induce mitochondrial stress such as expression and aggregation of mHtt. Based on our preliminary data we hypothesize that the activity of the proteasome regulated by PA200 has a so far unrevealed role in regulating mitochondrial homeostasis and in determining the equilibrium of protein aggregate formation in pathologic conditions. Thus in our ongoing projects we identify i) whether PA200 antagonizes the toxicity of mutant Htt expression, ii) the effect of mitochondrial Drp1 depletion on toxic Htt aggregate formation and iii) how ablation of PA200 elevates mitochondrial vulnerability upon mHtt stress. The characterization of PA200-proteasomes, the mitochondrial fission protein Drp1 and mHtt interplay using also clinical samples will provide us with more data about their physiological role and pathological effect on neurodegenerative diseases and will help to better understand and influence the disease.
Selected publications:
Lontay B, Kiss A, Virág L, Tar K. How Do Post-Translational Modifications Influence the Pathomechanistic Landscape of Huntington's Disease? A Comprehensive Review.
Int J Mol Sci. 2020 Jun 16;21(12):4282. doi: 10.3390/ijms21124282. PMID: 32560122
Douida A, Batista F, Robaszkiewicz A, Boto P, Aladdin A, Szenykiv M, Czinege R, Virág L, Tar K. The proteasome activator PA200 regulates expression of genes involved in cell survival upon selective mitochondrial inhibition in neuroblastoma cells.
J Cell Mol Med. 2020 Jun;24(12):6716-6730. doi: 10.1111/jcmm.15323. Epub 2020 May 5. PMID: 32368861
Aladdin A, Király R, Boto P, Regdon Z, Tar K. Juvenile Huntington's Disease Skin Fibroblasts Respond with Elevated Parkin Level and Increased Proteasome Activity as a Potential Mechanism to Counterbalance the Pathological Consequences of Mutant Huntingtin Protein.
Int J Mol Sci. 2019 Oct 26;20(21):5338. doi: 10.3390/ijms20215338. PMID: 31717806
Alatshan A, Kovács GE, Aladdin A, Czimmerer Z, Tar K, Benkő S. All-Trans Retinoic Acid Enhances both the Signaling for Priming and the Glycolysis for Activation of NLRP3 Inflammasome in Human Macrophage.
Cells. 2020 Jul 1;9(7):1591. doi: 10.3390/cells9071591. PMID: 32630207
Tar K, Dange T, Yang C, Yao Y, Bulteau AL, Salcedo EF, Braigen S, Bouillaud F, Finley D, Schmidt M. Proteasomes associated with the Blm10 activator protein antagonize mitochondrial fission through degradation of the fission protein Dnm1.
J Biol Chem. 2014 Apr 25;289(17):12145-56. doi: 10.1074/jbc.M114.554105. Epub 2014 Mar 6. PMID: 24604417
List of publications:
https://scholar.google.com/citations?user=eSpA7A8AAAAJ&hl=en&oi=ao
https://tudoster.idea.unideb.hu/hu/szerzok/3296