A team of researchers from the University of Saskatchewan has developed two caffeine-based chemical compounds that show promise in preventing the ravages of Parkinson’s disease.

Parkinson’s disease attacks the nervous system, causing uncontrolled shakes, muscle stiffness, and slow, imprecise movement, chiefly in middle-aged and elderly people. It is caused by the loss of brain cells (neurons) that produce dopamine, an essential neurotransmitter that allows neurons to “talk” to each other.

The team focused on a protein called α-synuclein (AS), which is involved in dopamine regulation.

In Parkinson’s sufferers, AS gets misfolded into a compact structure associated with the death of dopamine-producing neurons. Worse, AS appears to act like a prion disease (for example, variant Creutzfeldt-Jacob or “mad cow”). In prion diseases, one mis-folded protein triggers mis-folding in others, spreading like falling dominos.

Jeremy Lee, a biochemist from the U of S College of Medicine, and Ed Krol from the College of Pharmacy and Nutrition led the team, which included researchers Troy Harkness and Joe Kakish from the U of S College of Medicine, as well as Kevin Allen from the Drug Discovery and Research Group in the College of Pharmacy and Nutrition.

“Many of the current therapeutic compounds focus on boosting the dopamine output of surviving cells, but this is effective only as long as there are still enough cells to do the job,” Lee said. “Our approach aims to protect dopamine-producing cells by preventing α-synuclein from mis-folding in the first place.”

Although the chemistry was challenging, Lee explained the team synthesized 30 different “bifunctional dimer” drugs, that is, molecules that link two different substances known to have an effect on dopamine-producing cells. They started with a caffeine “scaffold,” guided by literature that shows the stimulant has a protective effect against Parkinson’s. From this base, they added other compounds with known effects: nicotine, the diabetes drug metformin, and aminoindan, a research chemical similar to the Parkinson’s drug rasagiline.

Using a yeast model of Parkinson’s disease, Lee and his team discovered two of the compounds prevented the AS protein from clumping, effectively allowing the cells to grow normally.

“Our results suggest these novel bifunctional dimers show promise in preventing the progression of Parkinson’s disease,” Lee said.

Funding: Funding for the research was provided through the Saskatchewan Health Research Foundation and the Natural Sciences and Engineering Research Council of Canada. The U of S Industry Liaison Office provided initial funding through its Proof of Concept Fund and has prepared a summary of the technology, inviting potential charitable funding and commercial partnerships to help develop it further.

Source: Jennifer Thoma – University of Saskatchewan
Image Source: This NeuroscienceNews.com image is for illustrative purposes only.
Original Research: Abstract for “Novel Dimer Compounds That Bind α-Synuclein Can Rescue Cell Growth in a Yeast Model Overexpressing α-Synuclein. A Possible Prevention Strategy for Parkinson’s Disease” by Joe Kakish, Kevin J.H. Allen, Troy A. Harkness, Edward Stanley Krol, and Jeremy Stuart Lee in ACS Chemical Neuroscience. Published online September 27 2016 doi:10.1021/acschemneuro.6b00209

Abstract

Novel Dimer Compounds That Bind α-Synuclein Can Rescue Cell Growth in a Yeast Model Overexpressing α-Synuclein. A Possible Prevention Strategy for Parkinson’s Disease

The misfolding of a-synuclein is a critical event in the death of dopaminergic neurons and the progression of Parkinson’s disease. Previously, it was suggested that drugs, which bind to α-synuclein and form a loop structure between the N- and C-termini tend to be neuroprotective, whereas others, which cause a more compact structure tend to be neurotoxic. To improve the binding to α-synuclein, eight novel compounds were synthesized from a caffeine scaffold attached to (R,S)-1-aminoindan, (R,S)-nicotine and metformin, and their binding to α-synuclein determined through nanopore analysis and isothermal titration calorimetry. The ability of the dimers to interact with α-synuclein in a cell system was assayed in a yeast model of PD which expressesAS-GFP (a-synuclein-Green Fluorescent Protein) construct under the control of a galactose promoter. In 5 mM galactose this yeast strain will not grow and large cytoplasmic foci are observed by fluorescent microscopy. Two of the dimers, C8-6-I and C8-6-N at a concentration of 0.1 υM allowed the yeast to grow normally in 5 mM galactose and the AS-GFP became localized to the periphery of the cell. Both dimers were superior when compared to the monomeric compounds. The presence of the dimers also caused the disappearance of preformed cytoplasmic foci. Nanopore analysis of C8-6-I and C8-6-N were consistent with simultaneous binding to both the N- and C-terminus of α-synuclein but the binding constants were only10^5 M-1.

“Novel Dimer Compounds That Bind α-Synuclein Can Rescue Cell Growth in a Yeast Model Overexpressing α-Synuclein. A Possible Prevention Strategy for Parkinson’s Disease” by Joe Kakish, Kevin J.H. Allen, Troy A. Harkness, Edward Stanley Krol, and Jeremy Stuart Lee in ACS Chemical Neuroscience. Published online September 27 2016 doi:10.1021/acschemneuro.6b00209