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Wednesday, October 5, 2022

Discovery reveals how Parkinson’s disease spreads in the brain

A new study led by researchers at Weill Cornell Medicine suggests that aggregates of the protein alpha-synuclein spread throughout the brains of Parkinson’s patients through cellular waste-clearing processes.

During a process called lysosomal exocytosis, neurons excrete protein waste that cannot be broken down and recycled. and may lead to new strategies to treat or prevent neurological disorders.

“Our results also indicate that lysosomal exocytosis may be a general mechanism for the processing of aggregated degradation-resistant proteins from neurons in normal, healthy environments and in neurodegenerative diseases. suggests” Feil Family Brain and Mind Research Institute and Appel Alzheimer’s Disease Research Institute at Weill Cornell Medicine.

Parkinson’s disease is a disorder in which neuronal death spreads in a characteristic pattern throughout the brain and usually progresses over decades. The disorder is best known for causing hand tremors, muscle stiffness, slowed gait, and other impairments of normal movement. However, it affects many areas of the brain and causes a variety of symptoms, including late-stage dementia. About 1 million people in the United States have Parkinson’s disease. Available treatments can relieve some movement disorders, but they cannot stop the disease from progressing. This is basically because researchers still don’t fully understand the process.

One of the key findings from decades of research into Parkinson’s disease is that neuronal death in this disease is due to the spread of abnormal aggregates of the neuronal protein alpha-synuclein in the brain. That’s it. This spread is an infection-like chain reaction process in which aggregates bind normal alpha-synuclein to them, and as they grow they divide into smaller aggregates that continue to multiply. Experiments in genus have shown that injecting these aggregates into the brain can initiate not only Parkinson’s disease-like neurodegeneration, but also this spread. However, the details of how neurons transmit them to other neurons have so far been poorly understood.

In this study, Sharma and his team, including co-first author Ying Xue Xie, a Ph.D. We have shown that it can cause degeneration and spread. – Occurs within neurons. These aggregates, which they found, accumulate within capsule-like waste containers within cells called lysosomes.

Lysosomes contain enzymes that can break down or “dissolve” proteins and other molecular waste into their constituent parts, essentially digesting and recycling them. However, the researchers found evidence that α-synuclein aggregates, which are tightly woven into tight-fitting overlapping structures called ‘amyloids’, are poorly degraded in lysosomes. Instead, it was often simply dumped from the original neuron.

In this process, exocytosis, lysosomes translocate to the plasma membrane and fuse, leaving the lysosomal contents unencapsulated and ejected intact into the fluid surrounding the cell. The findings help resolve a hotly debated issue in this area.

The researchers also showed in further experiments that the apparent concentration of diffusible aggregates could be reduced by reducing the rate of lysosomal exocytosis. Sharma said it hints at future approaches to treating Parkinson’s disease.

“We don’t know yet, but keeping these aggregates inside the lysosomes might improve neuronal health in the long run,” he said. “Some inherited disorders show similar impairments in lysosomal function, but these do not necessarily lead to Parkinson’s-level disease.”

Sharma said previous studies, including genetic studies, have linked lysosomal abnormalities not only to Parkinson’s disease, but to many other neurodegenerative diseases. It is a common mechanism for the spread of protein aggregates in disease, suggesting that it may be a general target for therapy and prevention.

He and his team are currently following up on research into the role of lysosomes in Alzheimer’s disease.

Jim Schnabel is a freelance writer for Weill Cornell Medicine.

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