A new study led by researchers at Weill Cornell Medicine says that clumps of the protein alpha-synuclein spread in the brains of people with Parkinson’s disease because of how cells get rid of waste. Lysosomal exocytosis is the process by which neurons expel protein waste that they are unable to digest and recycle. The discovery, which was published in Nature Communications on August 22, could help solve a mystery about Parkinson’s disease and lead to new ways to treat or prevent the neurological disease.
The study’s senior author, Dr. Manu Sharma, an assistant professor of neuroscience at the Feil Family Brain and Mind Research Institute and Appel Alzheimer’s Disease Research Institute at Weill Cornell Medicine, said, “Our results also suggest that lysosomal exocytosis could be a general mechanism for the disposal of aggregated and degradation-resistant proteins from neurons—in normal, healthy circumstances and in neurodegenerative diseases.”
Parkinson’s disease, which typically develops over decades, is characterized by the spread of neuronal death in a distinctive pattern throughout the brain. The symptoms of the illness that are most well-known are hand tremors, muscle rigidity, slowed gait, and other limitations of normal movement. However, it affects a wide range of brain areas, leading to a wide range of symptoms, including late-stage dementia. In the US, there are about 1 million people who have Parkinson’s. Researchers still don’t fully understand how the disease gets worse, so the treatments that are currently available can only help some movement problems for a short time.
One significant discovery from the past few decades of Parkinson’s research is that the spread of abnormal aggregates of the neuronal protein alpha synuclein within the brain is accompanied by the death of neurons in the disease. In a process akin to an infection, aggregates recruit normal alpha synuclein to join them, and as they enlarge, they shatter into smaller aggregates that spread further. Injecting these aggregates into the brain can start this spread as well as some Parkinson’s-like neurodegeneration, according to studies done on mice and non-human primates. But it has never been fully understood how neurons transmit information to other neurons.
In the study, Dr. Sharma and his team demonstrated that alpha synuclein aggregates—capable of spreading and causing neurodegeneration—originated within neurons using in-depth studies of Parkinson’s mouse models. They were joined by co-first author, Ying Xue Xie, a doctoral candidate at the Weill Cornell Graduate School of Medical Sciences. They found that these groups then gather inside lysosomes, which are waste containers in cells that look like capsules.
Enzymes found in lysosomes can “lyse,” or break down, proteins and other molecular waste into their component parts, effectively digesting and recycling them. But the scientists discovered proof that alpha synuclein aggregates, which are knit together with tight bonds in a close-fitting/snugly layered structure known as “amyloid,” are not broken down well within lysosomes; rather, they were frequently discovered to be simply dumped from their originating neurons. The lysosome travels to the cell membrane during this procedure, known as exocytosis, and joins it. As a result, the lysosome contents are released into the fluid surrounding the cell unencapsulated and in their original state. The discovery contributes to settling a contentious issue in the field.
In additional experiments, the researchers demonstrated that they could lower the apparent concentration of spread-capable aggregates by slowing the rate of lysosomal exocytosis. That, according to Dr. Sharma, points to a potential strategy for treating Parkinson’s.
According to him, neurons may benefit if they keep these aggregates inside of their lysosomes even in the long run. Even though some genetic disorders also affect the way lysosomes work, they may not get worse as quickly as Parkinson’s disease.
Dr. Sharma emphasized that previous research, including genetic studies, had connected lysosomal abnormalities to many other neurodegenerative diseases in addition to Parkinson’s. This suggests that lysosomal exocytosis may be a common way for protein aggregates to spread in these diseases, making it a possible target for generalized therapies and preventive measures.
He and his team are doing more research about how lysosomes work in Alzheimer’s disease right now.
