![Illustration of yeast cells during illumination with blue light. Credit: Max-Planck-Institut für Biochemie Prions induce toxic huntingtin oligomers](https://oponame.com/wp-content/uploads/2022/10/Prions-induce-toxic-huntingtin-oligomers.jpg)
Illustration of yeast cells during illumination with blue light. Credit: Max-Planck-Institut für Biochemie
Neurodegenerative diseases such as Alzheimer’s, Parkinson’s or Huntington’s disease are characterized by the deposition of clusters of proteins, called protein aggregates, in the brain of patients. Although disease-relevant proteins, such as the protein huntingtin in Huntington’s disease, are present in all human brain cells, huntingtin aggregates form in a specific region of the brain during the initial stage of the disease. .
A recent study by Ulrich Hartl’s group at the Max Planck Institute for Biochemistry investigates the influence that cell type has on this preference for aggregate formation in a distinct brain region. The study was published in the scientific journal molecular cell. To deal with this phenomenon, the researchers performed experiments in a yeast model system.
Artificial protein aggregation using blue light illumination
Similar to the human brain, the formation of huntingtin aggregates in yeast also depends on the cell type, the so-called yeast strain. While the huntingtin protein aggregates in some yeast strains, it remains soluble in others. Why this is the case has not been understood so far.
To study the distinction between different yeast strains and their contribution to the formation of huntingtin aggregates, the researchers used recent advances in the field of optogenetics. They biotechnologically manipulated yeast strains that normally do not allow huntingtin to aggregate and incorporated a molecular switch that could be activated with blue light. In this way, huntingtin aggregates could be formed simply by illuminating the cells with blue light.
Comparing yeast cells that naturally form huntingtin aggregates with those that only do so after activation with blue light surprised the researchers. Only in cells where huntingtin aggregates already form naturally, but not in cells where huntingtin aggregation was artificially induced by blue light, were toxic effects observed.
The study’s first author, Michael Gropp, opined that this phenomenon occurred because smaller intermediates, rather than large aggregates, are the actual toxic version of the protein. Only in yeast cells that naturally form huntingtin aggregates do these toxic little intermediates, the oligomers, exist. Here, large aggregates appear slowly, thanks to the accumulation of proteins around the smaller intermediates.
These small intermediaries are bypassed when huntingtin aggregation is artificially induced with blue light. Large aggregates then appear much more quickly, avoiding toxic effects.
The role of prions in the formation of aggregates
But why do some yeast strains form huntingtin aggregates, while other genetically identical strains do not? Further tests on yeast and experiments with purified proteins – artificially enriched proteins in a test tube – have helped researchers understand this phenomenon. Some yeast strains naturally contain protein aggregates of certain proteins, called prions.
These prion aggregates are not harmful to cells. However, due to their specific structure, these prion aggregates can influence soluble huntingtin proteins and impose their structure on them. As a result, soluble huntingtin proteins transform into an aggregated state. A side effect of this process is the appearance of toxic intermediates. Yeast strains that do not naturally form huntingtin aggregates also lack prions and are therefore unable to generate toxic intermediates, despite artificially inducing large huntingtin aggregates with blue light.
Possible Implications for Human Diseases
In recent years, many human proteins have been characterized that share similarities with yeast prions. Bioinformatics analysis of previously published datasets from mouse models and human cell cultures showed that mammalian proteins with such prion-like characteristics preferentially accumulate in neurons.
As an individual ages, they tend to form aggregates. The study authors suspect that aggregates of these prion-like proteins may in turn force the aggregation of disease-relevant proteins, such as huntingtin, in certain areas of the brain and thus contribute to disease progression. in neurodegenerative disorders. Further investigation into this hypothesis is still ongoing.
New light on protein aggregates and the diseases they cause
Michael H. M. Gropp et al, Formation of toxic polyQ-expanded huntingtin oligomers by prion-mediated cross-seeding, molecular cell (2022). DOI: 10.1016/j.molcel.2022.09.031
Provided by Max-Planck-Institut für Biochemie
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