How a simple plant protein could help clear Parkinson’s toxins
Liverwort-derived molecule triggers a 'cleanup' inside human nerve cells
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- A plant protein (MpEDC4) from liverwort shows promise for Parkinson's disease.
- It helps clear toxic alpha-synuclein protein clumps, a key factor in disease progression.
- This "molecular bridge" links harmful proteins to cellular recycling for degradation, offering a new treatment strategy.
A protein found in a common liverwort plant could be engineered to clear the toxic protein clumps associated with Parkinson’s disease, according to a new study.
Researchers discovered that this plant-based protein acts as a “molecular bridge,” successfully linking harmful alpha-synuclein to a human cell’s internal recycling system for degradation.
While studying how simple plants like Marchantia polymorpha dispose of cellular waste, scientists identified a specific protein called MpEDC4. This protein functions as a selective autophagy receptor, meaning it identifies unwanted material and directs it to the cell’s recycling machinery for breakdown and reuse.
When researchers introduced MpEDC4 into lab-grown human nerve cells, they found it significantly reduced levels of alpha-synuclein, which is the protein that accumulates into toxic clusters and contributes to the progression of Parkinson’s. This “cross-kingdom” discovery suggests that plant biology may hold the key to a new class of targeted treatments for Parkinson’s and other neurodegenerative diseases.
The search for a molecular holy grail
“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, PhD, a former group leader at the Gregor Mendel Institute (GMI) and now a professor at Heidelberg University, who co-led the study, said in a press release from the Austrian Academy of Sciences.
The study, “A lineage-specific selective autophagy receptor module mediates P-body turnover,” was published in Developmental Cell.
Cells constantly produce RNA molecules and proteins to carry out essential functions. At the same time, they must remove damaged, excess, or obsolete components to maintain internal balance. This cleanup relies on autophagy, a cellular recycling system that breaks down unwanted material and reuses its building blocks.
During autophagy, material to be removed is enclosed within a double-membrane structure called an autophagosome and transported within recycling vesicles, where it is broken down and recycled. While this process is well established, how specific cellular structures are selectively recognized and targeted for removal is less well understood.
One such structure is the P-body — a membraneless cluster of RNA and proteins that assembles and dissolves dynamically to help regulate gene expression in response to the cell’s needs. Although the mechanism by which P-bodies form is known, how they are specifically dismantled remains unclear.
To address this question, a research team led by Dagdas turned to Marchantia polymorpha, a simple liverwort widely used as a model organism in plant research.
The researchers identified MpEDC4, a core P-body component that acts as a selective autophagy receptor. In simple terms, this means the protein helps mark specific cellular structures — in this case, P-bodies — for removal by the cell’s recycling system.
Specifically, MpEDC4 was found to interact with ATG8, a protein that plays a key role in autophagy by helping recruit material into recycling vesicles. Through this interaction, MpEDC4 links P-bodies to the autophagy machinery, enabling their delivery for degradation. When this interaction was disrupted, P-bodies accumulated inside cells, confirming MpEDC4’s essential role in their selective clearance.
Around the same time, research led by Erinc Hallacli, PhD — who later joined the Max Perutz Labs at the Vienna BioCenter, neighboring the GMI, as junior group leader — identified a human counterpart to the plant protein, called EDC4. The human protein was found to interact with alpha-synuclein.
This finding prompted the two teams to hypothesize that MpEDC4 could facilitate alpha-synuclein degradation when introduced into human cells.
“We decided to collaborate and to investigate whether the plant EDC4 also interacts with alpha-synuclein and, crucially, whether it sends alpha-synuclein for degradation,” Hallacli said.
To test this, researchers introduced modified forms of either EDC4 or MpEDC4 into human cell models engineered to produce alpha-synuclein. The experiments confirmed a direct interaction between MpEDC4 and alpha-synuclein. More importantly, MpEDC4 significantly reduced alpha-synuclein levels, supporting a model in which it functions as an autophagy receptor that directs the toxic protein toward degradation.
By contrast, although EDC4 bound alpha-synuclein, it had no significant effect on its abundance. This suggested that only MpEDC4 engages the autophagy machinery in human cells.
Future steps for Parkinson’s therapy
The findings were further confirmed in cortical neurons generated from human induced pluripotent stem cells, lab-grown stem cells that can be turned into any body cell type.
Cortical neurons are primarily located in the cerebral cortex, which is the outer layer of the brain. In these neurons, again, only MpEDC4 promoted alpha-synuclein clearance.
“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 said.
The researchers described MpEDC4 as a “cross-kingdom” autophagy receptor — meaning that although it evolved in plants, it can function inside human neurons to promote the degradation of alpha-synuclein. Such findings suggest a potential new strategy for promoting the “targeted clearance of aggregation-prone proteins” in Parkinson’s and other neurodegenerative diseases, the researchers wrote.
The goal, Dagdas said, is to deliver a minimal, engineered version of the plant protein — containing only its essential functional components — specifically to the neurons most affected in Parkinson’s disease, where it could trigger targeted degradation of alpha-synuclein. The next steps will involve testing this approach in mouse models, he added.
