A plant protein is capable of dissolving protein aggregates related to various human pathologies

A team led by Núria Sánchez Coll, CSIC researcher at CRAG, has discovered that a protein from plants is able to clear aggregates of misfolded proteins. These protein clusters tend to accumulate in situations of prolonged stress, with aging and in various amyloid and neurodegenerative diseases.

The study has been published in the renowned journal The Plant Cell, and is the result of a collaboration led by CRAG with several international groups specialised in protein aggregation.

Mechanisms to fight stress and aging

In stressful situations, such as those caused by high temperatures, cells set in motion different highly controlled molecular mechanisms. One of these mechanisms is responsible for maintaining protein levels in order to preserve their essential functions. This involves stopping the synthesis of new proteins and activating the quality control mechanisms that ensure the correct folding of these molecules, which is directly related to their function. A key point in this process is to prevent the accumulation of misfolded proteins which in turn might form insoluble accumulations of aggregated proteins, that can be toxic to the cell.

In this context, CRAG researchers have discovered that the MC1 protein, from the metacaspases family, is present in the cellular structures called "stress granules" (SGs), which form inside plant cells in response to various stresses. SGs are accumulations of proteins and RNA molecules, and although the exact function is not known, it is believed that they serve to protect these molecules from harmful compounds produced during stressful conditions, preserving their function. SGs are dynamic structures, they form quickly when a stressful situation appears and dissolve when the stress subsides. This study shows that the MC1 protein participates in both the formation and the breakdown of these structures, which are of great importance to deal with stress efficiently without affecting the productivity of the plant.

«We have identified two regions of the MC1 protein, each important for a different process: either for the formation or for the dissolution of these SGs, a finding that can be useful when designing new plant varieties with a better response to stress», comments Núria Sánchez Coll, CRAG researcher responsible for the study.

On the other hand, the study also report the formation of SGs in plant aging conditions, something never described until now. The research team has observed that the increase in MC1 protein levels delays the effects of aging in leaves, increasing chlorophyll and decreasing the expression of genes involved in senescence. On the other hand, plants lacking MC1 age very quickly. This finding shows certain evolutionary parallels in the aging process between animals and plants, as it demonstrates that a correct control of functional protein levels in the cell and preventing aggregation are essential factors to delay aging. This fact opens the door to discovering new mechanisms that could help control this process.

Disaggregation of pathologically relevant proteins

In natural processes such as aging or due to a specific disease, the defense mechanisms mentioned above to combat stressful conditions do not work properly or are not as efficient, leading to various pathologies. Protein aggregation is a characteristic phenomenon of various neurodegenerative diseases such as Alzheimer's, Huntington's or Parkinson's. Despite the high incidence of these diseases, there are currently no effective therapies to treat them and it is a very complex field of study with many unknowns still to be resolved.

Given the role of MC1 in the dissolution of SGs, the research team tested its effect on various proteins that can form insoluble aggregates related to certain human pathologies. Indeed, in this study it has been shown that the MC1 protein is able to dissolve aggregates of at least three different proteins, one of them involved in transthyretin amyloidosis (a cardiac amyloid disease) and another in Huntington's disease. The researchers mixed in the lab the previously aggregated proteins together with the isolated MC1 protein, and observed an extraordinary decrease in the amount of aggregates compared to aggregate samples incubated without MC1. This fact means that the MC1 protein alone has the ability to get rid of these aggregates, without the need for the conditions found in the cellular environment. It should be noted that the activity of MC1 is directed specifically towards aggregated forms of the protein, since the proteins as such were not degraded.

This study, although preliminary, opens the door for a protein of plant origin to be used in strategies to fight both the effects of high temperatures in plants and the aggregation of proteins, a problem that is present in several human pathologies and neurodegenerative diseases of great importance.
Plants, being organisms that cannot move and escape the stresses caused by environmental conditions, have developed very efficient mechanisms to regulate and cope with stress at a molecular and cellular level. This is why they can be a source of very interesting biological mechanisms and processes that can serve as inspiration for new therapeutic tools and strategies. In addition, discoveries like those of this study can be useful for generating new plant varieties resistant to the extreme conditions caused by climate change.

Reference Article

Ruiz-Solaní, N., et al. Arabidopsis metacaspase MC1 localizes in stress granules, clears protein aggregates and delays senescence. The Plant Cell (2023). https://doi.org/10.1093/plcell/koad172

About the authors and funding of the study

Research at CRAG was supported by grants PID2019-108595RB-I00 funded by MCIN/AEI/10.13039/501100011033 and AGL2016-78002-R funded by CIN/AEI/10.13039/501100011033 and by ‘‘ERDF A way of making Europe’’ (to N.S.C. and M.V.); fellowship BES-2017-080210 funded by MCIN/AEI/10.13039/501100011033 and by ‘‘ESF Investing in your future’’ (to J.S.-L.); FPU19/03778 funded by MU (o Ministerio de Universidades) (to N.R.-S.); by the ‘‘Severo Ochoa Programme for Centres of Excellence in R&D’’ (SEV-2015-0533 and CEX2019-000902-S funded by MCIN/AEI/10.13039/501100011033); by the grant PID2020-119737GA-I00 funded by the Ministerio de Ciencia e Innovacion (MCIN/AEI/10.13039/501100011033) (to E.G.-B); by the Spanish Ministry of Science and Innovation (MICINN) grant PID2019-105017RB-I00 (to S.V.), by ICREA, ICREA-Academia 2020 (to S.V); by the MICINN fellowship (FPU17/01157) (to J.S.); and by the CERCA Programme/Generalitat de Catalunya. L.A. is supported by a Maria Zambrano postdoctoral fellowship by de Ministerio de Universidades and the European Union - NextGenerationEU.

• By CRAG
• 04/07/2023
• CRAG, MC1, SGs