Alpha-synuclein, a sticky and sometimes toxic protein involved in Parkinson’s disease (PD), blocks signals from an important brain growth factor, researchers have discovered.
The results were published this week in PNAS.
The finding adds to evidence that alpha-synuclein is a pivot for damage to brain cells in PD, and helps to explain why brain cells that produce the neurotransmitter dopamine are more vulnerable to degeneration.
Alpha-synuclein is a major component of Lewy bodies, the protein clumps that are a pathological sign of PD. Also, duplications of or mutations in the gene encoding alpha-synuclein drive some rare familial cases.
In the current paper, researchers led by Keqiang Ye, PhD demonstrated that alpha-synuclein binds and interferes with TrkB, the receptor for BDNF (brain derived neurotrophic factor). BDNF promotes brain cells’ survival and was known to be deficient in Parkinson’s patients. When applied to neurons, BDNF in turn sends alpha-synuclein away from TrkB. [Ye’s team has extensively studied the pharmacology of 7,8-dihydroxyflavone, a TrkB agonist.]
A “tug of war” situation thus exists between alpha-synuclein and BDNF, struggling for dominance over TrkB. In cultured neurons and in mice, alpha-synuclein inhibits BDNF’s ability to protect brain cells from neurotoxins that mimic PD-related damage, Ye’s team found. Read more
Our recent news item on Emory pathologist Keqiang Ye’s obesity-related researchÂ (Molecule from trees helps female mice only resist weight gain) understatesÂ how many disease models the proto-drugÂ he and his colleagues have discovered, 7,8-dihydroxyflavone, can be beneficial in.Â We doÂ mentionÂ that Ye’s partners in Australia and Shanghai are applying to begin phase IÂ clinical trials with a close relative of 7,8-dihydroxyflavone in neurodegenerative diseases.
Ye’sÂ 2010 PNAS paper covered models of Parkinson’s, stroke and seizure. Later publications take on animal models of depression, Alzheimer’s, fear learning, hearing lossÂ andÂ peripheral nerve injury. AlthoughÂ those findingsÂ begin to sound too good to be true, outside laboratories have been confirming the results (not 100 percent positive, but nothing’s perfect).Â Â Plenty of drugs don’tÂ make itÂ from animal models into the clinic, but this is a solid body of work so far.
Pathologist Keqiang Ye and his colleagues have been prolific in finding small molecules able to mimic the action of the brain growth factor BDNF. Aiming to export that success to similar molecules (that is, other receptor tyrosine kinases), they have been searching for potential drugs able to substitute for insulin.
Diabetes drugs Januvia (sitagliptin) and Lantus (insulin analog) are top 20 drugs, both in terms of dollars and monthly prescriptions, and the inconvenience of insulin injection is well known, so the business potential is clear.
A paper published in the journal Diabetes in April describes Yeâ€™s teamâ€™s identification of a compound called chaetochromin A, which was originally isolated by Japanese researchers studying toxins found in moldy rice. Chaetochromin A can drive down blood sugar in normal, type 1 diabetes and type 2 diabetes mouse models, the authors show.
See here for another compound identified in Ye’s labÂ with similar properties.
Peripheral nerve injury ranges from chronic irritation like carpal tunnel syndrome to violent trauma. Severe nerve injury can leave patients with lifelong disabilities. Even if nerves regenerate, functional recovery is often poor, because of problems with regeneration of axons, the signal-carrying â€œstalksâ€ of nerve cells.
Cell biologist Art English and his colleagues have shown that compounds identified by pathologist Keqiang Ye can promote axon regeneration when mice have injured peripheral nerves. The growth Cheap NFL Jerseys factor-mimicking compounds not only stimulate axons to regenerate twice as quickly (see figure), but also promote the restoration of connections between nerve and muscle. The results were published in September in PNAS.
Ye previously identified compounds that activate the same signals as the neuron growth factor BDNF (brain-derived neurotrophic factor). These compounds â€“ 7,8-dihydroxyflavone and deoxygedunin — have shown promise in experimental models of diseases such as stroke and Parkinsonâ€™s disease. They also have been used to tweak learning and memory in animal models.
Earlier this year, the FDA put limitations on some anti-diabetic drugs because of their cardiovascular risks. The prevalence of diabetes in the United States continues to increase and is now above 8 percent of the population, so the need for effective therapies remains strong.
Keqiang Ye, PhD
Pathologist Keqiang Ye and colleagues have a paper in the Journal of Biological Chemistry describing their identification of a compound that mimics the action of insulin. This could be the starting point for developing new anti-diabetes drugs.
The new research is an extension of the Ye laboratoryâ€™s work on TrkA and TrkB, which are important for the response of neurons to growth factors. Ye and Sung-Wuk Jang, a remarkably productive postdoc who is now an assistant professor at Korea University, developed an assay that allowed them to screen drug libraries for compounds that directly activate TrkA and TrkB. This led them to find a family of growth-factor-mimicking compounds that could treat conditions such as Parkinsonâ€™s disease, depression and stroke.
Since TrkA/B and the insulin receptor are basically the same kind of molecule — receptor tyrosine kinases– and use some of the same cellular circuitry, Ye and Jangâ€™s assay could also be used with the insulin receptor. Kunyan He and Chi-Bun Chan are the first two authors on the new paper. They report that the compound DDN can make cells more sensitive to insulin and improve their ability to take up glucose. They show that DDN (5,8-diacetyloxy-2,3-dichloro-1,4- naphthoquinone) can lower blood sugar, both in standard laboratory mice and in obese mice that serve as a model for type II diabetes.
Ye reports that he and his colleagues are working with medicinal chemists to identify related compounds that may have improved efficacy and potency.
â€œI hope in the near future we may have something that could replace insulin for treating diabetes orally,â€ he says.
Posted on October 7, 2011