Parkinson’s Origins Challenged: ‘Zombosomes’ May Spread Disease

A new study published in Cell Reports is challenging long-held beliefs about the origins of Parkinson’s disease. Research led by Anna Erlandsson at Uppsala University suggests the disease may not originate in the gut, as previously theorized, but instead spreads through the brain via cellular “taxi cabs” originating from brain cells called astrocytes.

For two decades, the “Braak hypothesis,” proposed in 2005 by Heiko Braak at the University of Frankfurt, has dominated understanding of Parkinson’s disease progression. This theory posited that the disease begins in the enteric nervous system (the gut) and gradually ascends to the brain via the vagus nerve, marked by the accumulation of a protein called alpha-synuclein. While the theory identified six stages of disease progression correlated with increasing severity, some individuals with advanced alpha-synuclein pathology showed no clinical signs of Parkinson’s, and the correlation between Braak stages and clinical severity wasn’t always consistent.

Recently, Alberto Espay at the University of Cincinnati published a critique of the Braak hypothesis in the Journal of Parkinson’s Disease, arguing that it conflated the concept of disease propagation with disease severity. He suggested the initial appeal of the theory—the elegant idea of a disease spreading from the gut to the brain—led to what he termed a “neuro-mythology” of Parkinson’s disease.

The Swedish study now provides further evidence supporting these criticisms. Researchers discovered that alpha-synuclein doesn’t travel along the vagus nerve, but is instead transported by structures called zombosomes. These are small, anucleated cells—meaning they lack a nucleus—that bud off from astrocytes, cells that provide support and protection to neurons. Zombosomes contain essential cellular components like mitochondria and vimentin filaments, enabling them to move and transport materials.

Astrocytes appear to attempt to clear the misfolded alpha-synuclein, a protein normally involved in neuronal communication, but become toxic when it misfolds. Zombosomes may represent a mechanism for astrocytes to dispose of this toxic protein, akin to discarding unwanted material. However, these cellular “packages” then travel to the brain, where even a single abnormal protein can trigger a prion-like chain reaction, leading to disease development.

The researchers found evidence of zombosome passage in the striatum, a brain region heavily implicated in Parkinson’s disease, identifying fragments of their cytoskeletons, organelles, and membranes. Further investigation using human brain organoids—three-dimensional cell cultures that mimic the structure and function of the brain—suggests zombosomes may also transport other misfolded proteins, such as tau, potentially linking them to Alzheimer’s disease as well.

Zombosomes aren’t unique; they share structural similarities with other known cellular structures involved in intercellular communication, such as migrasomes, blebbisomes, and exosomes. These structures play roles in various processes, including tumor metastasis and platelet function.

Understanding the normal function of zombosomes is a crucial next step, according to Professor Mario Zappia of the University of Catania, President of the Italian Neurological Society. He notes that astrocytes are also involved in the brain’s waste clearance system, known as the glymphatic system, which is most active during sleep. Astrocytes also regulate fluid flow within the brain, contributing to tissue repair and maintaining the blood-brain barrier. If zombosomes can transport aquaporin-4, a protein involved in fluid balance, as they do with alpha-synuclein, they could potentially act as “ambulances” to rapidly deliver repair mechanisms to damaged areas.

The discovery of zombosomes offers a new perspective on the pathogenesis of Parkinson’s disease and potentially other neurodegenerative disorders. While further research is needed to fully elucidate their role, these findings suggest that targeting zombosome activity could represent a novel therapeutic strategy. The research highlights the complex interplay between different brain cells in the development and progression of these debilitating conditions.