The fibrils that clump together in neurons and contribute to the progression of Parkinson’s disease may be undone by a protein complex called SCF. Recently discovered in cultured human cells and evaluated in mouse models of Parkinson’s, SCF is unstable and short-lived, but when it detects fibrils, it marks them for disposal. If SCF could be stabilized, its fibril-clearing capabilities could be enhanced, and the prospects for developing new, more effective therapies against Parkinson’s disease could be improved.

SCF, which stands for S-phase kinase-associated protein 1/cullin-1/F-box protein, is part of an adaptive response triggered by the neuronal uptake of α-synuclein fibrils. Significantly, this response is not triggered by α-synuclein monomers, oligomers, and dissociable fibrils.

These findings were obtained by scientists based at ETH Zurich. “Once the fibrils enter a new cell, they ‘recruit’ other alpha-synuclein molecules there, which then change their shape and aggregate together,” explained Paola Picotti, PhD, professor of the biology of protein networks at ETH Zurich. “This is how the fibrils are thought to infect cells one by one and, over time, take over entire regions of the brain.”

Besides determining that alpha-synuclein fibrils are the cell-invading and -corrupting culprits behind the spread of the α-synuclein aggregates, the scientists found that the fibrils are degraded by SCF after they are internalized by cells. Also, the scientists demonstrated that promoting ubiquitination counteracted the formation and spreading of α-synuclein aggregates in mouse models.

Detailed findings appeared June 5 in Science Translational Medicine, in an article titled, “A cullin-RING ubiquitin ligase targets exogenous α-synuclein and inhibits Lewy body–like pathology.” The article reports that S-phase kinase-associated protein 1 (SKP1), cullin-1 (Cul1), and the F-box/LRR repeat protein 5 (FBXL5) colocalized and physically interacted with internalized α-synuclein in cultured cells. It also describes the results of additional in vitro and in vivo evaluations.

“The SCF containing the F-box protein FBXL5 (SCFFBXL5) catalyzed α-synuclein ubiquitination in reconstitution experiments in vitro using recombinant proteins and in cultured cells,” wrote the article’s authors. “In both transgenic and nontransgenic mice, intracerebral administration of exogenous α-synuclein fibrils triggered a Lewy body–like pathology, which was amplified by SKP1 or FBXL5 loss of function.”

In this section of mouse brain, the right hemisphere shows the outcome of silencing a cullin-RING ubiquitin ligase. Inhibition of the Lewy body-like pathology triggered by exogenous α-synuclein fibrils is lost. [ETH Zurich/Natalia C. Prymaczok and Juan A. Gerez]

The ETH Zurich scientists anticipate that the SCF breakdown mechanism could be applied in therapy. “The more active the SCF complex, the more the α-synuclein fibrils are cleared, which could slow down or eventually stop the progression of such neurodegenerative diseases,” said Juan A. Gerez, PhD, a former postdoc in Picotti’s group. He added that the SCF complex is very short-lived, dissipating within minutes. Therapeutic approaches would focus on stabilizing the complex and increasing its ability to interact with alpha-synuclein fibrils. For example, drugs could be developed for this purpose.

Another approach to help Parkinson’s patients would be to transplant nerve stem cells into their brains, Picotti noted. Previous attempts haven’t been very successful, she explained, because the α-synuclein fibrils in the brain infected the healthy cells.

“If we can manage to modify the stem cells in such a way that they either don’t let fibrils in or that they immediately break down any fibrils they do let in, this could progress stem cell therapy,” she concluded.

Finally, gene therapy could be used to stabilize the SCF complex in nerve cells and thus increase its activity. “However, when it comes to potential therapies, we’re still right at the beginning,” Gerez admitted. “Whether effective therapies can be developed is still unclear.”

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