New findings may solve the mystery of Parkinson's disease

According to a recent study by scientists at Weill Cornell Medical College, protein-α synuclein aggregates spread
through the brains of Parkinson's disease patients through a process of cellular waste injection.

In this process, known as lysosomal exocytosis, neurons release protein waste
that cannot be broken down and recycled.
The findings, recently published in the journal Nature Communications, could unlock a mystery in Parkinson's and lead to new techniques
to treat or prevent the neurological disorder.

"Our findings also suggest that lysosomal exocytosis may be the general mechanism for processing aggregated and anti-degradable proteins from neurons — in normal, healthy environments and neurodegenerative diseases," said study senior author Dr.
Manu Sharma, assistant professor
of neuroscience at the Fairy Family Brain and Mind Institute and the Appel Alzheimer's Institute at Weill Cornell Medical College.

Parkinson's is a neurological disorder characterized by the loss of neurons throughout the brain in a pattern that usually lasts for decades
.
The most common symptoms of this disease are those that cause trembling hands, stiff muscles, a slowed gait, and other movement disorders
.
However, it affects a wide range of areas of the brain, causing a variety of symptoms, including advanced dementia
.
As of 2022, about 1 million people in the United States have Parkinson's disease
.
Because experts don't yet fully understand how the disease progresses, currently available treatments can only alleviate some movement abnormalities, not stop the disease from progressing
.

An important finding in Parkinson's research over the past few decades is that the death of neurons in this disease occurs with the spread of an abnormal aggregation in the brain of an abnormal collection of a neuronal protein, α alpha-synuclein
.
This diffusion is an infection-like chain reaction process in which aggregates induce normal α-synuclein to join it, splitting into smaller aggregates to continue spreading
as they become larger.
Experiments in mice and non-human primates have shown that injecting these aggregates into the brain triggers this transmission 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 candidate at Weill Cornell Graduate School of Medical Sciences, showed in detail in mouse models of Parkinson's that α — synuclein aggregates — capable of spreading and causing neurodegeneration — originate inside
neurons 。 They found that these aggregates accumulate
in sac-like waste bins in cells called lysosomes.

Lysosomes contain enzymes that break down protein and other molecular waste into building blocks, essentially digesting and recycling them
.
But the researchers found evidence that α-synuclein aggregates don't break down
well in lysosomes.
α-Synuclein aggregates are bound together in tight bonds to form a tight/comfortable layered structure called "amyloid"
.
Instead, they are often found simply discarded
from the original neuron.
In this process, known as exocytosis, lysosomes move to and fuse to the cell membrane so that the lysosomal contents are expelled as they are, without any encapsulation, into the
fluid surrounding the cell.
The discovery helps resolve a hotly debated issue
in the field.

The researchers also showed in further experiments that by reducing lysosomal exocytosis rates, they can reduce the apparent concentration
of diffusible aggregates.
Dr.
Sharma says this offers a way
to treat Parkinson's in the future.

"We don't know yet, but if neurons keep these aggregates in lysosomes, they may be better
off even in the long term," he said.
We see similar impairment of lysosomal function in some genetic diseases, but this does not necessarily lead to Parkinson's disease levels
.
”

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 diseases
.
This suggests that lysosomal exocytosis may be the general mechanism of protein aggregation and spread in these diseases and has the potential to be a general target for treatment and prevention
.
He and his team are now continuing to study the role of
lysosomes in Alzheimer's disease.

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