Venture into a world where the enigmas surrounding Parkinson’s disease, a daunting puzzle that has eluded scientists for generations, are slowly coming to light. At the core of this discovery is a tiny protein called α-synuclein, infamous for its pivotal role in the development of this debilitating disorder. Imagine this protein as a double agent, typically beneficial in the normal workings of our brain cells but somehow turning detrimental in Parkinson’s disease, leading to the deterioration of essential nerve cells. This breakthrough offers a fresh chapter in our understanding of Parkinson’s disease, unveiling the cellular intricacies within our brains and setting the stage for innovative treatments that could one day significantly improve the lives of those affected.

Peering into the depths of neurodegenerative challenges, an enlightening study conducted by lead researchers Dr. Tomoki Kuwahara and Professor Takeshi Iwatsubo, alongside their team Dr. Tetsuro Abe, Shoichi Suenaga, Dr. Maria Sakurai, and Dr. Sho Takatori, all from the University of Tokyo, illuminates the intricate mechanisms at play in Parkinson’s disease. Their work concentrates on the actions of α-synuclein, a key molecule in the puzzle of Parkinson’s, and its interaction with certain cellular pathways when cells are under stress.

Parkinson’s disease is characterized by the accumulation of α-synuclein aggregates in the brain, associated with the gradual loss of brain cells. Dr. Tomoki Kuwahara elaborated on their groundbreaking work, emphasizing that α-synuclein fibrils, once incorporated by cells, activate specific pathways that lead to the expulsion of these aggregates outside the cell. This fosters a cycle that might accelerate the spread of Parkinson’s disease pathology within the brain.

Their investigation uncovers a previously unseen behavior of α-synuclein, showing that stress within cell compartments called lysosomes prompts the release of harmful α-synuclein from immune cells in the brain. This process is steered through the action of another key protein LRRK2, encoded in the gene responsible for hereditary Parkinson’s disease, highlighting the link between genetic predispositions and the molecular onset of the disease.

α-Synuclein, typically aiding neuron function, changes under stress, leading to its aggregation. The team found that these aggregates could be released from cells via a mechanism involving small vesicles known as exosomes. This release process is particularly prominent in brain immune cells upon encountering internal stress, spotlighting a distinct response that may affect the disease’s trajectory.

Dr. Tomoki Kuwahara and the first author Dr. Tetsuro Abe shed more light, stating, “Stress within these cellular compartments induces the release of aggregated α-synuclein from brain immune cells, specifically through a cellular pathway involving LRRK2 and small vesicles.” These revelations offer a new angle on how Parkinson’s disease could evolve through processes beyond just neuron involvement. By showing the impact of internal cellular stress on the release of α-synuclein and implicating a particular cellular pathway in this process, the study reveals potential targets for therapeutic strategies. The opportunity to disrupt this cycle brings hope for treatments that could slow down or stop the progression of Parkinson’s disease, offering a brighter future for those grappling with this challenging condition.


Tetsuro Abe, Tomoki Kuwahara, Shoichi Suenaga, Maria Sakurai, Sho Takatori, Takeshi Iwatsubo. “Lysosomal stress drives the release of pathogenic α-synuclein from macrophage lineage cells via the LRRK2-Rab10 pathway.” iScience, February 16, 2024.