Discovery illuminates how Parkinson’s disease spreads in the brain

Aggregates of the protein alpha-synuclein spread in the brains of people with Parkinson’s disease through a cellular waste ejection process, a new study led by Weill Cornell Medicine researchers suggests.

During the process, called lysosomal exocytosis, neurons emit protein waste that they cannot break down and recycle. The discovery, published on 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 could be a general mechanism for the removal of aggregated and degradation-resistant proteins from neurons – in normal, healthy conditions and in neurodegenerative diseases,” said lead author Dr. Manu Sharma, an assistant professor of neuroscience in the Feil Family Brain and Mind Research Institute and Appel Alzheimer’s Disease Research Institute at Weill Cornell Medicine.

Parkinson’s is a condition that features the death of neurons in a characteristic pattern of distribution throughout the brain, which normally unfolds over decades. The disease is best known for causing hand tremors, muscle stiffness, slowed gait, and other limitations on normal movement. But it affects a wide range of brain regions, resulting in many different symptoms, including late-stage dementia. About 1 million people in the United States have Parkinson’s. Available treatments can alleviate some movement abnormalities, but don’t stop disease progression — mainly because researchers don’t fully understand that process yet.

A key finding from recent decades of Parkinson’s research is that neuron death in 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 where aggregates cause normal alpha-synuclein to join them and — as they grow — break down into smaller aggregates that continue to reproduce. Experiments in mice and non-human primates have shown that injecting these aggregates into the brain can initiate this spread, as well as some Parkinson’s-like neurodegeneration. But the details of how neurons pass them on to other neurons have never been well understood.

In the study, Dr. Sharma and his team, including co-first author Ying Xue Xie, a doctoral student at the Weill Cornell Graduate School of Medical Sciences, detailed studies of Parkinson’s mouse models indicate that alpha-synuclein aggregates — capable of spreading and causing neurodegeneration — – originate in neurons. These aggregates, they found, then accumulate in capsule-like waste bins in cells called lysosomes.

Lysosomes contain enzymes that can break down or “lyse” proteins and other molecular waste into their building blocks, essentially digesting and recycling them. But the researchers found evidence that alpha-synuclein aggregates, which are knitted together with tight bonds in a snug/snug-fitting layered structure called “amyloid,” do not break down properly in lysosomes; instead, they often turned out to be simply dumped from their original neurons. In this process, called exocytosis, the lysosome moves to the cell membrane and fuses with it, so that the contents of the lysosome are drained – 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 further experiments that by reducing the rate of lysosomal exocytosis, they could reduce the apparent concentration of aggregates that can disperse. That, said Dr. Sharma, suggests a future approach to treating Parkinson’s.

“We don’t know yet, but neurons may be better off, even in the long run, if they keep these aggregates in their lysosomes,” he said. “We see a similar deterioration in lysosomal function in some genetic disorders, but these do not necessarily lead to Parkinson’s disease.”

dr. Sharma emphasized that previous studies, including genetic studies, have linked lysosomal abnormalities not only to Parkinson’s, but also to many other neurodegenerative disorders. This suggests that lysosomal exocytosis may be a general mechanism for the proliferation of protein aggregates in these diseases – and possibly a common target for treatments and preventatives.

He and his team are currently investigating the role of lysosomes in Alzheimer’s disease.