Aggregates of the protein alpha-synuclein spread through the brains of people with Parkinson’s disease through a process of ejection of cellular waste, suggests a new study by researchers at Weill Cornell Medicine.
During the process, called lysosomal exocytosis, neurons eject protein waste that they cannot break down and recycle. The discovery, published August 22 in Nature Communicationcould solve one of the mysteries of Parkinson’s disease and lead to new strategies for treating or preventing the neurological disorder.
Our results also suggest that lysosomal exocytosis may be a general mechanism for the removal of aggregated and degradation-resistant proteins from neurons -; in normal, healthy circumstances and in neurodegenerative diseases. »
Dr. Manu Sharma, Study Lead Author, Assistant Professor of Neuroscience, Feil Family Brain and Mind Research Institute and Appel Alzheimer’s Disease Research Institute, Weill Cornell Medicine
Parkinson’s disease is a disorder characterized by the death of neurons in a characteristic pattern of spread in the brain, normally occurring over decades. The condition is best known for causing hand tremors, muscle stiffness, slowed walking, and other normal movement disorders. But it affects a wide range of brain regions, leading to many different symptoms, including late-stage dementia. About 1 million people in the United States have Parkinson’s disease. Available treatments may alleviate some movement abnormalities but do not halt disease progression, primarily because researchers do not yet have a full understanding of this process.
An important discovery that has emerged from the last decades of research on Parkinson’s disease is that the death of neurons in the disease follows the spread, in the brain, of abnormal aggregates of alpha synuclein, a neuronal protein. This spread is an infection-like chain reaction process in which the aggregates attract normal alpha-synuclein to join them and, as they grow, break into smaller aggregates that continue to spread. Experiments in mice and non-human primates have shown that injection of these aggregates into the brain can initiate this spread as well as some Parkinson-like neurodegeneration. But the details of how neurons transmit them to other neurons have never been fully understood.
In the study, Dr. Sharma and his team, including co-first author Ying Xue Xie, a doctoral candidate at the Weill Cornell Graduate School of Medical Sciences, showed with detailed studies of mouse models of Parkinson’s that the alpha synuclein aggregates; capable of spreading and causing neurodegeneration; originates in neurons. These aggregates, they found, then accumulate in capsule-shaped trash cans in cells called lysosomes.
Lysosomes contain enzymes that can break down or “lyse” proteins and other molecular wastes into their building blocks, essentially digesting and recycling them. But the researchers found evidence that alpha-synuclein aggregates, which are tightly bound in a tight-fitting layered structure called “amyloid,” are not broken down well in lysosomes; instead, they were often found to simply be dumped from their original neurons. In this process, called exocytosis, the lysosome moves towards the cell membrane and fuses with it, so that the contents of the lysosome are discharged – as is, without any encapsulation – into the fluid surrounding the cell. The finding helps resolve a hotly debated question in the field.
The researchers also showed in other experiments that by reducing the rate of lysosomal exocytosis, they could reduce the apparent concentration of propagating aggregates. This, said Dr. Sharma, suggests a future approach for the treatment of Parkinson’s disease.
“We don’t know yet, but neurons might be better off, even in the long run, if they retain these aggregates inside their lysosomes,” he said. “We see similar impairment of lysosomal function in certain genetic disorders, but these do not necessarily lead to a level of Parkinson’s disease.”
Dr. Sharma pointed out that previous studies, including genetic studies, have linked lysosomal abnormalities not only to Parkinson’s disease, but also to many other neurodegenerative disorders. This suggests that lysosomal exocytosis may be a general mechanism for spreading protein aggregates in these diseases and potentially a general target for treatments and preventive measures.
He and his team are currently pursuing studies on the role of lysosomes in Alzheimer’s disease.
Xie, YX, et al. (2022) Lysosomal exocytosis releases pathogenic α-synuclein species from neurons in models of synucleinopathy. Communication Nature. doi.org/10.1038/s41467-022-32625-1.