The brain exhibits a range of natural mechanisms for the clearance of various protein aggregates involved in neurodegenerative disease, both inside and outside the cells: clearance via immune cells; autophagy within cells; carried away via drainage of cerebrospinal fluid; and so forth. Clearly these mechanisms falter and become overwhelmed with advancing age, an outcome that results from a progressively increased burden of cell and tissue damage. Where a natural repair and maintenance mechanism exists, looking for ways to enhance that mechanism is one of the logical places to make a start on the development of viable therapies.
Aggregates of the protein alpha-synuclein in the nerve cells of the brain play a key role in Parkinson's and other neurodegenerative diseases. These protein clumps can travel from nerve cell to nerve cell, causing the disease to progress. Relevant for these diseases are long but yet microscopic fibres, or fibrils, to which large numbers of the alpha-synuclein molecules can aggregate. Individual, non-aggregated alpha-synuclein molecules, however, are key to the functioning of a healthy brain, as this protein plays a key role in the release of the neurotransmitter dopamine in nerve cell synapses.
When the protein aggregates into fibrils in a person's nerve cells - before which it must first change its three-dimensional shape - it can no longer carry out its normal function. The fibrils are also toxic to the nerve cells. In turn, dopamine-producing cells die, leaving the brain undersupplied with dopamine, which leads to typical Parkinson's clinical 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. This is how the fibrils are thought to infect cells one by one and, over time, take over entire regions of the brain."
Researchers were able to decipher a cellular mechanism that breaks down alpha-synuclein fibrils naturally. A protein complex called SCF detects the alpha-synuclein fibrils specifically and targets them to a known cellular breakdown mechanism. In this way, the spread of fibrils is blocked, as the researchers demonstrated in tests on mice: when the researchers switched off SCF's function, the alpha-synuclein fibrils were no longer cleared up in the nerve cells. Instead, they accumulated in the cells and spread throughout the brain.
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. The SCF complex is very short-lived, dissipating within minutes. Therapeutic approaches would focus on stabilising the complex and increasing its ability to interact with alpha-synuclein fibrils. For example, drugs could be developed for this purpose. "However, when it comes to potential therapies, we're still right at the beginning. whether effective therapies can be developed is still unclear."