Necroptosis, Autophagy and Parthanatos in the Pathogenesis of Brain Diseases

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Abstract

Necroptosis, autophagy and parthanatos are three interrelated mechanisms of programmed cell death that exert a significant impact on the health and pathology of the central nervous system. They participate in maintaining cellular homeostasis by eliminating damaged or nonfunctional cells, as well as in shaping the neuroinflammatory response. Dysregulation of these processes is associated with a range of neurological and psychiatric disorders – from neurodegeneration in Alzheimer’s and Parkinson’s diseases to depressive and schizophrenic conditions. This paper summarizes clinical and preclinical data describing the roles of necroptosis, autophagy and parthanatos in the pathogenesis of brain diseases. It also discusses experimental models that enable the study of these forms of cell death and the testing of new therapeutic approaches. A thorough understanding of the molecular mechanisms underlying these processes opens up opportunities for the development of drugs capable of simultaneously modulating multiple signaling pathways, thereby improving the prevention, diagnosis, and treatment of central nervous system disorders.

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About the authors

N. I. Golushko

Almazov National Medical Research Center; Saint Petersburg State University

Email: avkalueff@gmail.com
Russian Federation, Saint Petersburg; Saint Petersburg

D. D. Martynov

Almazov National Medical Research Center; Saint Petersburg State University

Email: avkalueff@gmail.com
Russian Federation, Saint Petersburg; Saint Petersburg

A. S. Lebedev

Almazov National Medical Research Center; Saint Petersburg State University; Sirius University of Science and Technology

Email: avkalueff@gmail.com
Russian Federation, Saint Petersburg; Saint Petersburg; Sirius Federal Territory

N. P. Ilyin

Almazov National Medical Research Center; Saint Petersburg State University

Email: avkalueff@gmail.com
Russian Federation, Saint Petersburg; Saint Petersburg

D. S. Galstyan

Almazov National Medical Research Center; Saint Petersburg State University

Email: avkalueff@gmail.com
Russian Federation, Saint Petersburg; Saint Petersburg

A. V. Kaluev

Almazov National Medical Research Center; Saint Petersburg State University; Sirius University of Science and Technology

Author for correspondence.
Email: avkalueff@gmail.com
Russian Federation, Saint Petersburg; Saint Petersburg; Sirius Federal Territory

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2. Fig. 1. Schematic representation of the main signalling pathways leading to necroptosis, autophagy and parthanatos in CNS cells, including the interaction of TNFR with RIPK1/RIPK3 and MLKL, the role of PARP1/AIF in DNA damage, and the participation of PARG in PAR degradation, which affects the energy balance of the cell. The role of adaptor and regulatory proteins (FADD, TRADD, etc.) in switching different forms of programmed death is also shown.

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3. Fig. 2. Main biological features and intersections of the three pathways of cell death - parthanatos, autophagy and necroptosis - based on the data used in this article, as well as taking into account information from works specialising in the differences and similarities of the listed processes [56, 201].

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