Pathologist Keqiang Ye and colleagues recently published a paper in PNAS that may have implications for Parkinson’s disease pathology and treatment strategies.
The protein alpha-synuclein is a bad actor in PD (nice explainer from Michael J. Fox Foundation); it’s a major constituent of Lewy bodies, the protein clumps that appear in PD patients’ brains, and there is a genetic link too. Alpha-synuclein seems to bring other proteins into the clumps, which may disrupt neuron function.
In particular, it sequesters PIKE-L, an inhibitor of AMP kinase, leading to AMP kinase hyperactivation and cell death. AMP kinase is a metabolic regulator activated by metformin, a common treatment for diabetes. So activating AMP kinase in some situations can be good for your body; however for the neurons affected by alpha-synuclein, activating it too much is bad.
The title of Keqiang Yeâ€™s recent Nature Communications paper contains a provocative name for an enzyme: delta-secretase.
Just from its name, one can tell that a secretase is involved in secreting something. In this case, that something is beta-amyloid, the toxic protein fragment that tends to accumulate in the brains of people with Alzheimerâ€™s disease.
Aficionados of Alzheimerâ€™s research may be familiar with other secretases.Â Gamma-secretase was the target of some once-promising drugs that failed in clinical trials, partly because they also inhibit Notch signaling, important for development and differentiation in several tissues. Now beta-secretase inhibitors are entering Alzheimerâ€™s clinical trials, with similar concerns about side effects.
Now, many Alzheimerâ€™s researchers have studied gamma- and beta-secretase, but a review of the literature reveals that so far, only Ye and his colleagues have used the term delta-secretase.
This enzyme previously was called AEP, for asparagine endopeptidase. AEP appears to increase activity in the brain with aging and cleaves APP (amyloid precursor protein) in a way that makes it easier for the real bad guy, beta-secretase, to produce bad beta-amyloid.*Â At Alzforum, Jessica Shugart describes the enzyme this way:
Like a doting mother, AEP cuts APP into bite-sized portions for toddler BACE1 [beta-secretase] to chew on, facilitating an increase in beta-amyloid production. 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 studying the functions of an enzyme called AEP, or asparagine endopeptidase, in the brain. AEP is activated by acidic conditions, such as those induced by stroke or seizure.
AEP is a protease. That means it acts as a pair of scissors, snipping pieces off other proteins. In 2008, his laboratory published a paper in Molecular Cell describing how AEPâ€™s acid-activated snipping can unleash other enzymes that break down brain cellsâ€™ DNA.
Following a hunch that AEP might be involved in neurodegenerative diseases, Yeâ€™s team has discovered that AEP also acts on tau, which forms neurofibrillary tangles in Alzheimerâ€™s disease.
â€œWe were looking for additional substrates for AEP,â€ Ye says. â€œWe knew it was activated by acidosis. And we had readÂ in the literature that the aging brain tends to be more acidic, especially in Alzheimerâ€™s.â€
The findings, published in Nature Medicine in October, point to AEP as a potential target for drugs that could slow the advance of Alzheimerâ€™s, and may also lead to improved diagnostic tools. Read more
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 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.
Treatment strategies for several types of cancer have been transformed by the discovery of â€œtargeted therapies,â€ drugs directed specifically against the genetic mutations that drive tumor growth. So far, these strategies have been relatively unsuccessful when it comes to glioblastoma, the most common and most deadly form of brain tumor affecting adults. Glioblastoma was one of the first tumor types to be analyzed in the Cancer Genome Atlas mega-project, but many of the molecular features of glioblastoma have been difficult to exploit.
For example, about 40 percent of glioblastoma tumors have extra copies of the EGFR (epidermal growth factor receptor) gene. EGFR provides a pedal-to-the-metal growth signal and is known to play a role in driving the growth of lung and colon cancers as well. But drugs targeted against EGFR that have extended patient survival in lung cancer have shown disappointing results with glioblastoma. The reason: the tumor cells can quickly mutate the EGFR gene or switch to reliance on other growth signals.
Keqiang Ye, PhD and colleagues recently described the discovery of a compound that may be valuable in fighting glioblastoma. The Emory researchers devised a scheme to stop tumor cells from using well-known escape routes to avoid EGFR-based drugs. Their results are published in the journal Science Signaling. Postdoctoral fellow Kunyan He, PhD, is the first author.
The compound they identified inhibits the enzyme JAK2, one of the apparent escape routes taken by glioblastoma cells. The compound can pass the blood-brain barrier and inhibit glioblastoma growth while having low toxicity, the researchers report.
Pathologist Keqiang Ye and his colleagues have identified a new potential drug target in Alzheimerâ€™s disease. Itâ€™s called SRPK2 (serine-arginine protein kinase 2).
Keqiang Ye, PhD
Depleting this enzyme from the brain using genetic engineering tools alleviates cognitive impairment in an animal model of Alzheimerâ€™s. The result suggests that drugs that target this enzyme could be valuable in the treatment of Alzheimerâ€™s, although additional studies on human brain samples are necessary to fully confirm the findings, Ye says.
The results were published Tuesday in Journal of Neuroscience. The first author is postdoctoral fellow Yi Hong.
Hong and colleagues found that SRPK2 has elevated activity in a mouse model of Alzheimerâ€™s. It acts on tau, one of the two major toxic clumpy proteins in Alzheimerâ€™s. (beta-amyloid is outside the cell and forms plaques, tau is inside and forms tangles). Previous research on SRPK2 indicated that it had something to do with RNA splicing, so its â€œentanglementâ€ with tau is a surprise.
Over the last few years, pathologist Keqiang Ye and his colleagues have displayed an uncanny talent for finding potentially useful medicinal compounds. Recently another example of this talent appeared in Journal of Biological Chemistry.
Keqiang Ye, PhD
Postdoctoral fellow Qi Qi is first author on the paper. Collaborators include Jeffrey Olson, Liya Wang, Hui Mao, Haian Fu, Suresh Ramalingam and Shi-Yong Sun at Emory and Paul Mischel at UCLA.
Qi and Ye were looking for compounds that could inhibit the growth of an especially aggressive form of brain cancer, glioblastoma with deletion in the tumor suppressor gene PTEN. Tumors with this deletion do not respond to currently available targeted therapies.
The researchers found that acridine yellow G, a fluorescent dye used to stain microscope slides, can inhibit the growth of this tumor:
Oral administration of this compound evidently decreases the tumor volumes in both subcutaneous and intracranial models and elongates the life span of brain tumor inoculated nude mice. It also displays potent antitumor effect against human lung cancers. Moreover, it significantly decreases cell proliferation and enhances apoptosis in tumors…
Optimization of this compound by improving its potency through medicinal chemistry modification might warrant a novel anticancer drug for malignant human cancers.
Ye’s team observed that acridine yellow G appears not to be toxic in rodents. However, the acridine family of compounds tends to intercalate (insert itself) into DNA and can promote DNA damage, so more toxicology studies are needed. Other acridine family compounds such as quinacrine have been used to treat bacterial infections and as antiinflammatory agents, they note.
A paramecium stained with acridine orange, which shows anticancer activity for tumors containing PTEN mutations
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