Don't let the cell grow old – control the quality of proteins!
Agglutination and protein accumulation in nerve cells are the main signs of age-related neurodegenerative diseases, such as Alzheimer's disease.
Therefore, cell survival depends on the controlled removal of excess protein. Scientists from Johannes Gutenberg University Mainz have discovered exactly how certain proteins regulate protein breakdown during the aging process.
Each protein of our cells has a certain life span. After this period or even earlier (for example, in response to the harmful effects of external factors, such as oxidative stress), proteins are destroyed through a certain process of protein degradation. The number of proteins requiring elimination may increase under conditions of prolonged oxidative stress, as it happens during the aging process or in neurodegenerative diseases.
Damaged proteins that cannot be neutralized by cellular "protein purification plants" tend to accumulate, thereby threatening the life of the cell. Nerve cells are particularly sensitive to such protein accumulation, and protein agglutination in nerve cells is a characteristic pathological symptom of a variety of age-related neurodegenerative diseases in humans, such as Alzheimer's disease and Parkinson's disease. Thus, for the normal existence of the cell, effective control over the quality of the protein is necessary.
It has long been known that this quality control mechanism changes with cell aging, but only now Professor Christian Behl and his colleagues from the Institute of Pathological Chemistry at the University of Mainz (Institute of Pathobiochemistry of Mainz University) have found indisputable evidence of this. They were able to pinpoint proteins that, at the molecular level, regulate both potential cellular protein degradation pathways – proteasomal and lysosomal. Scientists were able to show how the control function of these proteins changes during cell aging.
Published on February 19 in the journal EMBO (Gamerdinger et al., Protein quality control during aging involves recruitment of the macroautophagy pathway by BAG3), these findings, based mainly on the doctoral research of Martin Gamerdinger, are of great importance for understanding the pathogenesis of age-related neurodegenerative diseases. "We will be able to discover and study the exact causes of age-related neurodegenerative diseases such as Alzheimer's disease, as well as develop appropriate treatment only after a thorough analysis of the molecular changes occurring during aging of the nerve cell. Alzheimer's disease is mainly characteristic of elderly people; it occurs and progresses in old nerve cells," emphasizes Christian Bel, thereby confirming the importance of Harmerdinger's discovery.
The study was also attended by Professor Uwe Wolfrum from the Institute of Zoology at the Johannes Gutenberg University in Mainz and Professor Ulrich Hartl from the Max Planck Institute of Biochemistry in Martinsried near Munich. They focused on determining the special role of BAG1 and BAG3 proteins in protein degradation during aging.
Scientists were able to prove that BAG1 and BAG3 regulate proteasomal and lysosomal protein destruction pathways, respectively. "Interestingly, in the process of cell aging, there is a transition from BAG1 to BAG3, and this activates the lysosomal pathway of protein destruction – the so-called macroautophagy pathway," explains study leader Martin Gamerdinger. He began his work by studying human fibroblasts, and then successfully transferred the data obtained to nerve cells. A much more powerful, BAG3 pathway of macroautophagy becomes predominant with aging of the rodent brain; scientists believe that this kind of change may be a way to compensate for the increased concentration of damaged proteins in old cells.
The dysfunction of this molecular switch, as the body ages, can cause a malfunction of the cellular "protein purification plant" and the subsequent accumulation of proteins in nerve cells, which occurs in human neurodegenerative diseases. Scientists plan to study this in more detail in the course of subsequent studies, when special models of diseases will be used.
Portal "Eternal youth" www.vechnayamolodost.ru16.03.2009