Cells survive by constantly clearing away molecular waste. Studying a liverwort, Yasin Dagdas and his group at the GMI of the OeAW and the Heidelberg University have now uncovered a mechanism that not only explains how unusual membraneless cellular structures are recycled but also points to a new strategy for breaking down the toxic protein causing Parkinson’s disease.
Cells work like a well-run city: Construction never stops, but neither does demolition. RNA molecules are produced and proteins are built, but damaged or unneeded components must be cleared away before they clog up the cell. For their waste removal, cells rely on autophagy, literally “self-eating”. In this cleaning and recycling program, the cell wraps any waste in a bag – the autophagosome – and delivers it to the vacuole, where components are broken down and reused.
Until now, scientists have not known how rather peculiar structures in the cell, so-called P-bodies, are degraded and recycled. Many cellular functions are organized in organelles, clearly defined compartments hemmed in by lipid membranes. P-bodies are different: Although the structures are visible under the microscope, they are not enclosed by a membrane. Instead, these clusters of RNA and proteins assemble and dissolve dynamically, depending on the cell’s needs. In his newest study, Yasin Dagdas and colleagues formerly at the Gregor Mendel Institute of Molecular Plant Biology and now at Heidelberg University, together with Elif Karagoz and Erinc Hallacli at the Max Perutz Labs identify how these transient, unwrapped structures are recognized, captured and delivered to the cell’s recycling machinery in the liverwort Marchantia polymorpha. Unexpectedly, the identified plant protein turns out to send human alpha-Synuclein, the protein that damages neurons in Parkinson’s disease, for degradation – cracking a holy grail in neurodegeneration.
Plant protein sends neurodegenerative protein to the trash
Initially, Dagdas and colleagues, including first author and PhD student Alibek Abdrakhmanov, searched for molecules that act as a bridge between P-bodies and the cell’s waste removal machinery. One molecule they identified was the receptor MpEDC4. The researchers found this receptor to bind RNA and protein components within P-bodies, while simultaneously interacting with the forming waste bag, the autophagosome.
As often in science, serendipity had a hand in the next discovery: Just as the Dagdas team was wrapping up its study, another group reported a counterpart existing in human cells, called EDC4. This human EDC4 interacts with alpha-synuclein, the protein that accumulates in Parkinson’s disease. In neurons, alpha-synuclein forms toxic aggregates that clog up the neurons and ultimately lead to their death, causing the typical symptoms of Parkinson’s disease.
“Finding a way to degrade alpha-synuclein – and similar proteins in other neurodegenerative diseases, such as tau in Alzheimer’s disease – has been a holy grail in neurodegeneration research”, Yasin Dagdas says. In a further coincidence, Erinc Hallacli, who had identified human EDC4 and its link with alpha-synuclein, moved his group to the neighboring Max Perutz Labs at the Vienna BioCenter. “We decided to collaborate and investigate whether the plant EDC4 also interacts with alpha-synuclein and, crucially, whether it sends alpha-synuclein for degradation.”
Hallacli and his lab turned human induced pluripotent stem cells into cortical neurons. The researchers then placed human EDC4 and Marchantia MpEDC4 into these neurons, which contain alpha-synuclein. Like in the natural setting, the human EDC4 bound but did not send alpha-synuclein for degradation. By contrast, the Marchantia MpEDC4 not only bound alpha-synuclein, but also caused alpha-synuclein to be degraded. “The plant protein acts as a bridge: It binds alpha-synuclein and it binds to the cell’s autophagy machinery, sending alpha-synuclein to be broken down”, Dagdas summarizes.
Tinkering with evolution
This striking observation could lead to new therapeutic strategies for neurodegenerative diseases. Dagdas is planning to test a minimal version of the plant protein – which contains only the most essential parts needed for the protein to still work – in mice. The goal is to deliver the protein specifically to the neurons most affected in Parkinson’s disease, where it could trigger the degradation of alpha-synuclein.
For Dagdas, this work is also a reminder not to underestimate plants. “Cells across all domains of life face similar challenges: They need to manage waste, defend against pathogens, maintain order under stress. Evolution, as the biologist François Jacob put it, does not produce novelties from scratch, it works on what already exists.” By studying how one domain of life solves a problem, Dagdas wants to uncover strategies that may be adapted to another domain. “We want to engineer pathways by learning solutions from one organism and bringing this feature into another one.”
Publication
A lineage-specific selective autophagy receptor module mediates P-body turnover, Alibek Abdrakhmanov, Elizabeth Ethier, Aleksandra S. Anisimova, Nenad Grujic, Ranjith K. Papareddy, Marion Clavel, G. Elif Karagöz, Erinc Hallacli, Yasin Dagdas, Developmental Cell, 2026.
DOI: 10.1016/j.devcel.2026.01.017
Scientific Contact
Yasin Dagdas
Gregor Mendel Institute
Austrian Academy of Sciences
yasin.dagdas(at)gmi.oeaw.ac.at