A new study led by Weill Cornell Medicine researchers indicates that aggregates of the alpha-synuclein protein spread in the brains of people with Parkinson’s disease through a process of expulsion of cellular waste.
During this process, known as lysosomal exocytosis, neurons excrete protein waste that they cannot break down and recycle. The discovery was published on August 22 in Nature CommunicationsIt could solve one of the mysteries of Parkinson’s disease and lead to new strategies to treat or prevent the neurological disorder.
Dr. Manu Sharma, an assistant professor of neuroscience at the Feil Family Brain and Mind Research Institute and the Appel Alzheimer’s Institute for Alzheimer’s Disease Research at Weill Cornell Medicine, said the study’s senior author.
Parkinson’s disease is a disorder that shows neuronal cell death in a characteristic pattern that spreads through the brain, usually unfolding over decades. This disease is notorious for causing hand tremors, muscle stiffness, slow walking, and other impairments in normal movement. But it affects a wide range of areas of the brain, resulting in many different symptoms, including dementia in the later stages. Approximately one million people in the United States have Parkinson’s disease. Available treatments can relieve some movement abnormalities but not stop disease progression — mainly because researchers don’t yet have a complete understanding of the process.
One important discovery that has emerged in the past few decades of Parkinson’s disease research is that the death of neurons in the disease follows the spread, within the brain, of abnormal pools of alpha-synuclein, a neurotransmitter protein. This diffusion is an infection-like chain reaction process in which aggregates induce natural alpha-synuclein to join them, and as they grow larger they split into smaller aggregates that continue to multiply. Experiments with mice and non-human primates have shown that injecting these aggregates into the brain can initiate this spread, as well as some neurodegeneration similar to Parkinson’s disease. But the details of how neurons transmit it to other neurons are never well understood.
In the study, Dr. Sharma and his team, including co-first author Ying Xue Xie, a doctoral candidate at Weill Cornell Graduate School of Medical Sciences, demonstrated in detailed studies of Parkinson’s mouse models in which alpha-synuclein aggregates — capable of spreading and causing neurodegeneration — originated within cells. nervousness; They found that these aggregates then accumulate inside capsule-like waste bins in cells called lysosomes.
Lysosomes contain enzymes that can break down, or “lyse,” the proteins and other molecular waste in their building blocks, essentially digesting them and recycling them. But the researchers found evidence that α-synuclein aggregates, held together by tight bonds in a closely spaced/relaxed layered structure called amyloid, do not disintegrate well within lysosomes; Instead, they are often found simply from the neurons in which they originated. In this process, called exocytosis, the lysosome travels to the cell membrane and fuses with it, so that the contents of the lysosome are discharged – as they are, without any encapsulation – into the fluid surrounding the cell. This discovery helps solve one of the hotly debated questions in the field.
The researchers also showed in other experiments that by decreasing the rate at which lysosomal cells exit, they can reduce the apparent concentration of aggregates capable of spreading. Dr. Sharma said this points to a future approach to treating Parkinson’s disease.
“We don’t know yet, but neurons may be better off, even in the long run, if they keep these aggregates within their lysosomes,” he said. “We see similar impairments in lysosomal function in some genetic disorders, but these do not necessarily lead to the level of Parkinson’s disease.”
Dr. Sharma emphasized 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 of total protein ubiquitylation in these diseases—and perhaps a general goal for therapeutics and prevention.
He and his team are currently pursuing studies of the roles of lysosomes in Alzheimer’s disease.