It has been known for a while that the aggregation of misfolded proteins in cells can cause disease. However, a new framework for protein aggregation has been created by scientists at Stowers Institute for Medical Research. Published 16 October, the results detail an astonishing finding about the aggregates of misfolded cellular proteins in the brains of those affected by neurodegenerative diseases, such as Parkinson’s disease.

The mechanistic explanation for the correlation between misfolded proteins and neurodegenerative diseases is that as a result of mutations, that accumulate as we age, the subtle balance of the synthesis, folding, and degradation of proteins, is disturbed resulting in the production and aggregation of misfolded proteins.

The researchers at the Stowers Institute for Medical Research revealed that 90 percent of aggregates form on the surface of the endoplasmic reticulum (ER), a location of protein synthesis in the cell. Prior to this study, it was thought that misfolded proteins spontaneously clump together in the cytosol, the fluid component of a cell’s interior.

In the study led by Rong Li, 3D time lapse movies were used to visualise what the misfolded proteins did in yeast cells. Rong Li then stated that “[their] findings have challenged the notion of the aggregation process as a passive consequence of accumulating misfolded proteins”.

To perform this study, scientists used heat and other forms of stress to induce misfolded proteins to clump together in budding yeast Saccharomyces cerevisae – an idealised model organism frequently used in protein-protein interaction networks.

It was found that aggregation of damaged or misfolded proteins is a protective mechanism against proteotoxic stress, abnormalities of which underlie many aging-related diseases.

It was shown in this study that in asymmetrically dividing yeast cells, aggregation of cytosolic misfolded proteins does not occur spontaneously but requires new polypeptide synthesis and is restricted to the surface of ER, which harbours the majority of active translation sites.

Protein aggregates formed on ER are frequently also associated with or are later captured by mitochondria, greatly constraining aggregate mobility.

The cell’s ‘power house’, the mitochondria, plays a vital role in the mobility of these protein aggregates. “We found the majority of aggregates on the surface of ER were in regions where ER and mitochondria come together, which is surprising but fits well with the view of regulated aggregation,” says Zhou.

Scientists identified the quality control mechanism that limits the spreading of the misfolded protein aggregates to the bud and thereby the daughter cell. During mitosis, aggregates are tethered to well-anchored maternal mitochondria, whereas mitochondria acquired by the bud are largely free of aggregates.

Disruption of aggregate-mitochondria association resulted in increased mobility and leakage of mother-accumulated aggregates into the bud. “As such, the bud-inherited mitochondria were largely devoid of aggregates.” says Li.

Based on this study, cells with advanced replicative age exhibit gradual decline of aggregates-mitochondria association, likely contributing to their diminished ability to rejuvenate through asymmetric cell division.

This has been a surprise discovery that may overturn decades of thinking about how the body fixes proteins that come unravelled and it also greatly increases opportunities for therapies to prevent diseases such as Parkinson’s.

Astrid Nardecchia

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