Neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's disease are characterized by the deposition of protein clumps in patients' brains, known as protein aggregates. Although disease-relevant proteins, such as the huntingtin protein in Huntington's disease, are present in all cells of the human brain, huntingtin aggregates form in a specific region of the brain during the early stages of the disease.
|Illustration of yeast cells under blue light illumination. Max-Planck-Institute für Biochemie|
Ulrich Hartl's group at the Max Planck Institute of Biochemistry recently investigated the impact of cell type on this preference for aggregate formation in a specific brain region. The findings were published in the journal Molecular Cell. The researchers conducted experiments in a yeast model system to investigate this phenomenon.
Blue light illumination induces artificial protein aggregation
The formation of huntingtin aggregates in yeast, like that of the human brain, is dependent on the cell type, or yeast strain. In some yeast strains, the huntingtin protein aggregates, but in others, it remains soluble. So far, no one knows why this is the case.
The researchers used recent advances in optogenetics to investigate the differences between different yeast strains and how they contribute to the formation of huntingtin aggregates. They biotechnologically manipulated yeast strains that do not normally allow huntingtin aggregation and integrated a molecular switch that could be activated by blue light. Huntingtin aggregates could be formed in this manner simply by illuminating the cells with blue light.
The researchers were taken aback when they compared yeast cells that naturally form huntingtin aggregates to those that only do so after being activated with blue light. Toxic effects were observed only in cells where huntingtin aggregates form naturally, not in those where huntingtin aggregation was artificially induced with blue light.
Michael Gropp, the study's first author, reasoned that this phenomenon occurred because smaller intermediates, rather than large aggregates, are the actual toxic version of the protein. These smaller toxic intermediates, known as oligomers, exist only in yeast cells that naturally form huntingtin aggregates. Large aggregates form slowly here as proteins accumulate around the smaller intermediates.
When huntingtin aggregation is induced artificially with blue light, these small intermediates are bypassed. Large aggregates appear much faster, avoiding toxic effects.
The role of prions in the formation of aggregates
But why do some yeast strains form huntingtin aggregates and others that are genetically identical do not? Additional yeast assays and experiments with purified proteins—proteins that were artificially enriched in a test tube—aided the researchers in comprehending this phenomenon. Certain yeast strains naturally contain protein aggregates of specific proteins, known as prions.
These prion aggregates are not toxic to cells. However, due to their specific structure, these prion aggregates can influence and impose their structure on soluble huntingtin proteins. As a result, soluble huntingtin proteins begin to aggregate. The appearance of toxic intermediates is a side effect of this process. Despite the artificial induction of large huntingtin aggregates with blue light, yeast strains that do not naturally form huntingtin aggregates do not possess prions and thus are unable to generate toxic intermediates.
Possible consequences for human disease
Many human proteins with similarities to yeast prions have been identified in recent years. Bioinformatic analysis of previously published data sets from mouse models and human cell cultures revealed that prion-like mammalian proteins preferentially accumulate in neurons.
They tend to form aggregates as an individual's age increases. The study's authors believe that prion-like protein aggregates can force the aggregation of disease-relevant proteins, such as huntingtin, in specific brain areas, contributing to disease progression in neurodegenerative disorders. This hypothesis is still being researched further.
Journal information: Molecular Cell