when the brain processing system gets stuck

The cells that make up our brains are like small towns. Inside it is the base – the nucleus, where the personality and function of the cell are encoded in the form of genes and regulatory elements.

Information from this nucleus and external stimuli will determine whether the cell will be a neuron responsible for the transmission of neural information, or whether it will belong to the glial line, which is involved in conditioning, facilitating and optimizing the work of neurons. In any case, the data encoded in the nucleus will determine not only the origin, but also the appearance and function of the cell.

The end product of a gene is a protein, the basic building block of life. There is a wide variety of proteins in the cell, and their synthesis and processing will depend on their purpose and final destination. Some will function as structural support for cell walls or membranes; others will participate in communication between cells, receiving, amplifying and sending signals; and finally, some will specialize in folding, transporting, or breaking down other proteins.

Thus, proteins are not only the main participants in the activity of the cell city, but also the targets for the action of drugs in the event of a disorder or disease.

processing and updating

The protein code is not static, that is, proteins and the structures formed by them, such as cell organelles – mitochondria, ribosomes, cytoplasm … – do not persist throughout the life of the cell. On the contrary, both are renewed gradually as part of the maintenance of cellular machinery.

This renewal is possible due to the delivery of macromolecular structures to the lysosome – the “cell destroyer” – through a process called autophagy, which means “eating oneself.” Lysosomes contain acids and proteins that break down all kinds of cellular macromolecules (large molecules), including fats, sugars, genetic material, and other proteins.

Thus, this mechanism allows the synthesis of new proteins after processing. That is why it plays a key role in the maintenance and renewal of cells at all stages of brain life.

Quality service issues

When the cellular shredder fails, damaged proteins and other cellular debris accumulate. It is the trigger mechanism for lysosomal storage diseases – rare pathologies that are transmitted by genetic inheritance. Because of the importance of cell renewal from an early age, these ailments usually begin during childhood.

Affected organisms lose the ability to break down certain types of cellular components, usually proteins and fats with sugary components, making them easier to accumulate in the lysosomal compartments. Consequently, the ability to renew is lost, resulting in disorder and disease.

Gaucher’s disease is the most common lysosomal storage pathology. It is inherited as a result of mutations (present in both parents) in the gene responsible for the production of the protein glucocerebrosidase (GBA). This causes a significant decrease or lack of activity of GBA, which is responsible for the breakdown of sweet fats.

In some cases, fat and sugar waste accumulates in nerve cells, which causes deterioration of cognitive, motor and autonomic (breathing, blood pressure…) brain functions. This is mainly due to changes in local connections or synapses of neurons, as well as in lipid structures that isolate neuronal processes and provide high-speed transmission. These are processes that depend on the optimal functioning of the autophagic and lysosomal renewal pathways.

New hope for Parkinson’s disease

In recent years, an association between Gaucher’s disease and Parkinson’s disease has been described. Mutation of one copy of the GBA gene is not enough to form the first, but it is the most important genetic risk factor for Parkinson’s disease.

It is estimated that more than 8.5 million people in the world suffer from this disorder, making it the most common movement disorder. The cause of 85% of cases is unknown, with age being the main risk factor along with other genetic and/or environmental triggers.

Movement symptoms (tremors, stiffness, difficulty starting to move…) are the most common, but they can also affect cognitive and autonomic functions of the brain, as well as lysosomal storage diseases.

Among the genetic risk factors that make a significant contribution to the development of Parkinson’s disease is not only, as we indicated, the mutation of the gene encoding the GBA protein, but also other genes associated with the regulation of autophagic and lysosomal networks. This supports the evidence that disruption of these pathways contributes to the neurological deficits caused by sporadic Parkinson’s disease.

Restoring the function of proteins associated with the regulation of the brain chopper, more specifically GBA, may alter the onset and/or progression of Parkinson’s and Gaucher’s disease.

This is where ambroxol, a classic mucolytic drug with the ability to refold the mutant GBA protein, can come to the rescue. Various studies have shown that Ambroxol can increase the degrading activity of sweet fats with the help of GBA, improving the traffic flow of autophagic and lysosomal networks.

Clinical trials are currently underway to test the effectiveness of Ambroxol, and we will find out in the coming years whether this research work will improve the quality of life of patients and their families.

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