An enzyme called MARK2 was identified as a major stress response mutation in cells in a study by researchers at the Johns Hopkins Bloomberg School of Public Health. Abstinence of this type of stress response is a potential cause of brain cell injury in neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and Amyotrophic Lateral Sclerosis. This discovery will make MARK2 a research focus for its potential role in these diseases, and may ultimately serve as a target for the treatment of neurodegenerative diseases.
In addition to its potential relevance to neurodegenerative diseases, the discovery is a breakthrough in understanding basic cell biology.
The paper outlining the discovery will appear online March 11 in PLoS Biology.
The study focused on a cellular response to “proteotoxic” stress – a buildup of damaged or complete proteins within the main part of the cell, which is a key feature of neurodegenerative diseases. Cells are known to respond to this type of stress by reducing the production of new proteins, and a signaling enzyme appears to mediate this response. The researchers, after regulating the enzyme of other markers, were able to show that the signaling enzyme MARK2 has this role.
Further studies of this previously unknown signaling pathway should broaden our understanding of protein regulation in cells and the role of this process in the development of human disease. “
Jiou Wang, PhD, Professor, Department of Biochemistry and Molecular Biology, Bloomberg School
Together, Alzheimer’s, ALS, and other neurodegenerative disorders affect more than 50 million people worldwide. So far there is no treatment for the onset of a disease, let alone a cure, for any of them – especially as their causes are not well understood.
One set of possible causes of neurodegenerative disorders relates to the proteotoxic stress and the response in brain cells. When this response is activated, reducing protein synthesis, it is best to reduce the protein burden of the cell under proteotoxic pressure, thus allowing it to overcome the stress. But the long – term reduction of protein synthesis could end a cell ‘s hunger for needed proteins, injure them, and cause cell death. In other cases, failure of the proteotoxic stress response, rather than overeating, may be the problem, so that too much protein leads to cell injury or death.
To fully understand each situation, scientists need to understand the signaling pathway that senses proteotoxic stress and alters the proteotoxic stress response. Wang and his colleagues wanted in their new study to find out about it.
Like others in this field, the research team already knew that the molecule at the end of this pathway that alters protein production is a member of a broad class of signaling enzymes called kinases. They also knew in advance that there are a number of specific kinases that suppress protein production in the same way, but in response to other types of cell pressure, such as viral infection. The challenge in this study was to find the specific kinase that triggers this inversion in response to proteotoxic stress in a key part of the cell.
The researchers first identified the MARK2 kinase as one of several candidates for their research by sifting through a large database, extracted by prior research, of various kinases and the proteins involved. they could be involved. Following the lead with various cell-free experiments and cell culture, they were able to show that MARK2, or any other kinase candidate, cannot shut down the protein-making mechanism in cells in response to proteotoxic stress, even when the other four know there are no protein-blocking kinases.
Looking up the signaling pathway, the team found that MARK2 is activated by another sign kinase, PKCδ, which is available for its MARK2-activating role under conditions of proteotoxic stress, thus effectively acting as proteotoxic pressure sensor.
As an initial study of the clinical appropriateness of these findings, the researchers examined a mouse model of familial ALS and samples of spinal cord material from human ALS patients. They found evidence that this PKCδ-MARK2 pathway is highly active in these cases compared to non-ALS mice and humans.
“These findings are consistent with the notion that in ALS, for example, this PKCδ-MARK2 pathway is highly active and reduces protein production, which, over the long term, contributes to the disease process, ”Wang says.
Having clarified the basics of how this pathway works, Wang and colleagues now plan to study it in different neurodegenerative disease models to see if the pathway could be adopted. aimed at treating such diseases.
“I suspect that this PKCδ-MARK2 pathway will eventually be shown to be relevant not only in neurodegenerative disorders but in several other diseases including cancers, “Wang says.
Source:
Johns Hopkins University Bloomberg School of Public Health