Scientists analyzed studies on neurodegenerative diseases such as Alzheimer's, Huntington's and dementia with Levi's corpuscles, and found out what an important role three proteins of the PIDDOSOME complex play in them, triggering the process of programmed cell death. Thus, mutations in two of them — PIDD1 and RAIDD — lead to abnormalities in brain development, and an excess of the third — caspase-2 — contributes to the appearance of pathological proteins in the nervous tissue. The work can be used in the creation of new drugs for the treatment of neurodegenerative diseases. The results of the study, supported by a grant from the Russian Science Foundation (RNF), are published in the journal Trends in Molecular Medicine.

The cells of our body are constantly being updated: some die, others appear. One of the most studied variants of cell death is apoptosis. This is a programmable process that prevents the reproduction of cells in the body with any disorders. So, if a cell does not function properly, processes of "self-destruction" are triggered in it, which regulate special enzymes called caspases. Interestingly, the caspases initiating apoptosis do not work alone, but in complexes with helper proteins. For example, caspase-2 forms a complex with PIDD1 and RAIDD proteins called PIDDosome, which, in fact, is involved in triggering apoptosis. However, studies indicate that the PIDDosome can work not only for the benefit of the body, but also in certain cases lead to neuropathologies.

The staff of the V.A. Engelhardt Institute of Molecular Biology (Moscow) and Lomonosov Moscow State University (Moscow) analyzed research papers in which a link was established between the components of the PIDDosome and the development of neurodegenerative diseases in order to better understand what role these proteins play in the appearance of disorders.

"Neurodegenerative diseases are various pathologies characterized by dysfunction and continued loss of neurons, glial cells and neural networks in the brain and spinal cord, which causes certain problems related to movement, memory and the ability of a person to speak and breathe. Alzheimer's, Huntington's, and dementia with Lewy bodies are some of the most striking examples of such pathologies. Modern methods of treatment have limited effectiveness and only help to slow down their progression," says Alexey Zamaraev, a participant in the project supported by an RNF grant, the lead author of the article, a researcher at the V.A. Engelhardt Institute of Molecular Biology and the Laboratory for the Study of Apoptosis Mechanisms at Lomonosov Moscow State University.

Analysis of the available data has shown that mutations in the genes encoding the PIDD1 and RAIDD proteins often lead to abnormalities in brain development, in particular, to smoothing the convolutions of the cerebral cortex. This, in turn, is expressed in mental retardation, mental and behavioral problems.

Other studies have indicated that an excess of caspase-2 in the brain leads to the accumulation of specific proteins-amyloids, which serve as markers of the above neurodegenerative diseases.

Thus, PIDDosome components can serve as a promising therapeutic target for the treatment of neurodegenerative diseases and other brain lesions. Moreover, the authors described real examples when PIDDosome proteins were used for these purposes. Thus, experiments on mice have shown that suppressing the activity of caspase-2 helps restore memory and cognitive functions of animals suffering from Alzheimer's, Huntington's, and dementia with Levi's corpuscles.

"Laboratory studies have already allowed us to find a number of compounds that, by acting on various components of the PIDDosome, help fight the signs of neurodegenerative diseases. Subsequent preclinical and clinical trials will help to better evaluate their effectiveness and, possibly, introduce them into clinical practice," concluded Pavel Volik, a participant in the project supported by the RNF grant, a postgraduate student of the Department of Biochemistry and Regenerative Biomedicine of Lomonosov Moscow State University and a laboratory assistant at the V.A. Engelhardt Institute of Molecular Biology.

In the future, the authors will have to study in more detail whether mutations in PIDD1 and RAIDD affect the assembly of the PIDDosome and how exactly they lead to disorders of brain development.

photo: Inhibition of PIDDosome components as a method of combating neurodegenerative diseases. Source: Pavel Volik

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