Researchers have uncovered a shared brain cell breakdown mechanism behind Alzheimer’s and Parkinson’s diseases, revealing how two different proteins can disrupt neurons in the same devastating way.

Parkinson’s disease and Alzheimer’s disease are attributed to the buildup of two key proteins, ⍺-synuclein and tau, respectively. Even though these proteins are typically found in healthy brains, they can misfold and spread in a “prion-like” way, causing nearby proteins to misfold too. This gradually damages the communication between neurons, especially at the tiny connection points, or synapses, where they pass messages to each other.

A new study by researchers from the Okinawa Institute of Science and Technology (OIST) in Japan has discovered that, although the proteins are different in Alzheimer’s and Parkinson’s, they use the same mechanism to cause harm to neurons.

“Synapses are communication hubs in the brain involved in different neuronal circuits controlling different functions,” said lead and corresponding author Dimitar Dimitrov, of OIST’s Synapse Biology Unit. “Therefore, protein accumulation in synapses of one neuronal circuit may impact memory, while in another it may impair motor control. This helps to explain how a shared mechanism of synaptic dysfunction can lead to the distinct symptoms of both Alzheimer’s and Parkinson’s diseases.”

The researchers grew neurons from mice and humans in the lab. They added preformed fibrils (pffs), clumps of the misfolded forms of ⍺-synuclein and tau, to the lab-grown neurons. These fibrils acted like “seeds,” causing the neurons’ own proteins to start misfolding and accumulating, mimicking what happens in neurodegenerative diseases like Parkinson’s or Alzheimer’s.

After two weeks, the researchers examined where the proteins accumulate and what changes occurred in the cells’ structure and function, especially involving the microtubules (the internal “scaffolding” of neurons) and vesicle recycling (how neurons reuse the small packets that release neurotransmitters). They also tested whether boosting autophagy, the cell’s waste-disposal and recycling process, could prevent this buildup.

The researchers noted that both ⍺-synuclein and tau built up inside neurons, particularly in synapses where communication happens. There was excessive growth of microtubules that wasn’t caused by an increase in gene activity, but likely due to the cells failing to clear away old or misfolded proteins.

There was also an accumulation of p62, a marker protein that accumulates when autophagy is impaired. When the researchers stimulated autophagy, the problem improved. Neurons rely on endocytosis, the recycling of tiny vesicles that carry neurotransmitters. Imaging showed that endocytosis was slowed down dramatically after ⍺-synuclein or tau buildup.

“When disease-related proteins accumulate in brain cells, they cause overproduction of protein filaments called microtubules, which are normally essential in cell structure and function,” Dimitrov said. “When over-produced, these microtubules trap a protein called dynamin, which is responsible for the retrieval of emptied vesicles from cell membranes, playing a crucial role in vesicle recycling. With less dynamin, vesicle retrieval and recycling slow, thereby interrupting signaling and communication between brain cells.”

Even though Parkinson’s and Alzheimer’s diseases involve different proteins, this study suggests they may harm neurons through the same process, disrupting vesicle recycling at synapses. Since proper vesicle recycling is crucial for brain communication, this mechanism could explain why patients experience diverse symptoms – from movement problems to memory loss – depending on which brain regions are affected first. The discovery may also have therapeutic value.

“Preventing disease-related protein accumulation, stopping microtubule over-production, or disrupting microtubule-dynamin bindings – our new mechanism identifies three potential therapeutic targets common across Parkinson’s and Alzheimer’s disease,” said OIST Professor Emeritus Tomoyuki Takahashi, the study’s senior author. “Research like this is important to develop new treatments that ease the impact of these diseases on patients, families, and society as a whole.” The study was published in The Journal of Neuroscience.

Source: OIST