ETH researchers break down pathological protein aggregates

“Aggregates of the protein alpha-synuclein in the nerve cells of the brain play a key role in Parkinson’s and other neurodegenerative diseases,” writes the ETH in a statement. On the one hand, this protein plays a key role in the release of the neurotransmitter dopamine in nerve cell synapses. Bound in long fibres known as fibrils, it is toxic to dopamine-producing cells. As a result, the brain is undersupplied with dopamine, which leads to typical Parkinson’s symptoms such as muscle tremors.

“Once the fibrils enter a new cell, they ‘recruit’ other alpha-synuclein molecules there, which then change their shape and aggregate together,” explains Paola Picotti, Professor of the Biology of Protein Networks at ETH Zurich, in the statement. “This is how the fibrils are thought to infect cells one by one and, over time, take over entire regions of the brain.”

Picotti and her research colleagues at the ETH have also deciphered a cellular mechanism that breaks down alpha-synuclein fibrils naturally. Within the mechanism, a protein complex called SCF detects the alpha-synuclein fibrils specifically and targets them to a cellular breakdown mechanism.

“The more active the SCF complex, the more the alpha-synuclein fibrils are cleared, which could slow down or eventually stop the progression of such neurodegenerative diseases,” adds research group lead Juan Gerez. “However, when it comes to potential therapies, we’re still right at the beginning.”

First, therapeutic approaches would focus on stabilizing the very short-lived SCF complex and increasing its ability to interact with alpha-synuclein fibrils.