Slowing the Spread of Disease-causing Protein with "foldamers"
The progressive nature of Parkinson’s disease (PD) is due in part to the spread of a misfolded protein called alpha-synuclein through the brain. Alpha-synuclein forms clumps that clog up brain cells (i.e., neurons), leading to their eventual degeneration. These clumps can also spread from neuron to neuron and trigger the misfolding of other functional alpha-synuclein in those new destinations. Sunil Kumar, PhD, a recipient of a Parkinson’s Foundation Stanley Fahn Junior Faculty Award, has identified a potential new way to stop this spread through the use of a biomimicry approach. In this approach, they use a class of ligands called “foldamers”, which mimic the chemical and structural fingerprints of the clumping alpha-synuclein and inhibit this toxic process.
In his lab at the University of Denver in Colorado, Dr. Kumar will further investigate and refine the design of his these foldamers. These foldamers are bioengineered compounds that aredesigned to physically wrap around other proteins and inhibit their toxic functions. One of these foldamers has proven itself to be especially good at wrapping around misfolded alpha-synuclein and preventing their spread in petri dish, roundworm and mice models of PD.
Next, Dr. Kumar will inject different doses of the foldamer into mice experiencing PD-like symptoms due to spreading alpha-synuclein clumps to find a minimum dose. He will then look at how the treatment affects neuronal health, motor function and overall survival in these PD-like mice compared to controls. If the foldamer works as intended, the treated mice should show improvement as the foldamer stops misfolded alpha-synuclein spread.
Then, Dr. Kumar will tune the design of this foldamer by altering various key features to see if he can improve the foldamer’s capability to restrain misfolded alpha-synuclein. These variations will be tested in Dr. Kumar’s previously utilized petri dish and roundworm PD models, comparing their effectiveness to the original design. If any work better, he will test them in the mouse model as well.
Dr. Kumar is thrilled at the opportunity to investigate the potential of PD foldamer therapies with the support of this Stanley Fahn Junior Faculty Award: “This award means a lot for an assistant professor who is starting a career in the field of Parkinson’s disease and will give me the opportunity to try new ideas, which will further establish my career in this field.”
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