04 February 2014

An aging brain needs to be looked after

Rarely used in modern English, the word "chaperone" originally referred to an elderly lady accompanying a young girl to balls and monitoring her behavior. In biology, this term means a type of proteins that protect cells from abnormally altered proteins considered to be involved in the development of neurodegenerative diseases. Sometimes chaperones are called heat shock proteins, because their protective effect was first discovered when studying temperature stress.

Researchers at Emory University, working under the leadership of Shihua Li, have demonstrated that as animals age, their brains become more susceptible to the action of abnormal proteins, which is partly due to a decrease in the activity of one of the chaperones. The authors also identified potential therapeutic targets, exposure to which will protect the brain from the toxic effects of abnormal proteins.

The authors conducted experiments on a mouse model of spinal-cerebellar ataxia, but the results obtained may help to understand the mechanisms of development of other diseases, including Alzheimer's disease and Parkinson's disease.

Spinal-cerebellar ataxia is a hereditary neurodegenerative disease characterized by gait disorders occurring in middle age and loss of the ability to coordinate movements due to cerebellar atrophy (Latin cerebellum). There are several types of disease caused by different mutations. Most of these mutations lead to the appearance of the so–called polyglutamine blocks in the ataxin protein molecule - multiple repetitions of the amino acid glutamine. This disrupts the functions of the protein and increases the propensity of its molecules to form aggregates.

The cause of Huntington's disease is also the appearance of polyglutamine repeats in the sequence of the huntingtin protein. Abnormally altered proteins are also involved in the development of Alzheimer's disease and Parkinson's disease, but their formation is the result of triggering other mechanisms. However, in all cases, abnormally altered proteins are toxic and interfere with the normal functioning of unchanged protein molecules.
Initially, the authors suggested that the severity of spinal-cerebellar ataxia is due to the duration of the accumulation period of abnormal proteins, that is, age. However, experiments have shown that this is not the case. It turned out that in old animals, after starting the synthesis of abnormal protein, its accumulation and development of the disease occurs much faster than in young ones. This indicates a greater susceptibility of aging neurons to the toxic effects of an abnormally altered protein.

The search for the causes of the age-related increase in susceptibility led the authors to chaperones, whose function is to prevent incorrect binding of "sticky" regions of protein molecules with other molecules. It turned out that as the brain cells age, there is a significant decrease in the activity of chaperone Hsc70, while the activity of other proteins of this class does not change with age.

To confirm the role of the Hsc70 protein, the researchers stimulated its synthesis in brain cells by introducing a viral vector carrying the Hsc70 gene into the cerebellum of animals. This significantly increased the ability of cells to utilize abnormally altered protein molecules and slowed down neurodegeneration.

The authors also found that abnormally altered ataxin interferes with the production of a growth factor known as MANF (from the English mesenchephalic astrocyte-derived neurotrophic factor – mesencephalic neurotrophic factor of astrocytes), while an increase in the synthesis of chaperone Hsc70 prevents this. Moreover, the introduction of a viral vector encoding the MANF gene can also slow down neurodegeneration.

The authors believe that small molecules that increase the production of chaperone Hsc70 or MANF growth factor may become effective drugs for the treatment of spinal-cerebellar ataxia in the future.

Article by Su Yang et al. Age-Dependent Decrease in Chaperone Activity Impairs MANF Expression, Leading to Purkinje Cell Degeneration in Inducible SCA17 Mice is published in the journal Neuron.

Evgeniya Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru based on the materials of Emory University:
Aging brains need 'chaperone' proteins.


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