Researchers from the University of Cambridge in England report promising results for trehalose in models of both Huntington's and Parkinson's. Dr. LaVonne Veatch Goodman reviews this report that focuses on trehalose benefit shown in a cellular system called autophagy. This mode of action now joins a growing list of cellular benefits for this safe treatment; in fact, scientists have now described more neuroprotective mechanisms triggered by trehalose than any other agent studied in HD models.
The Goal To test and describe the ability of trehalose, a natural sugar, to induce or stimulate autophagy, which is the way cells get rid of bulk debris. In this process, a "Pac man" like structure called an autophagosome finds and destroys cellular garbage including toxic proteins and damaged mitochondria. The authors describe how this process decreases levels of toxic protein fragments and improves survival in laboratory cell models of Huntington's and Parkinson's disease.
The Method Scientists used several types of cells engineered to express mutant huntingtin protein. In each case, cells formed huntingtin aggregates and caused premature cell death. The researchers then added trehalose to the culture medium on the outside of cells or added it to the inside of cells (by using cells engineered to produce trehalose) and compared the difference in aggregate number and survival between trehalose treated and untreated cells. In yet more experiments, scientists compared trehalose effects to that of rapamycin, a drug that researchers have shown previously to stimulate autophagy [Ravikumar B 2006].
The Results Researchers found that trehalose stimulated autophagy, decreased aggregate number, and improved survival of treated cells. They also demonstrated decreased levels of mutant huntingtin protein and its smaller toxic fragments. Scientists also found decreased levels of mitochondrial molecules (cytochrome c and complex 1V) that are markers of cell injury as had been seen in earlier experiments with rapamycin. The researchers then showed that trehalose and rapamycin work at different sites in the autophagy mechanism, and that the combination works better than either agent alone.
Why is it Important? Any treatment that decreases the level of mutant huntingtin protein in brain cells will treat the root cause of Huntington's disease. As the authors show in this elegant study, this can be accomplished (in cell models) by using trehalose or rapamycin to increase the destruction of mutant huntingtin and its fragments. Important for those who suffer from HD, both trehalose and rapamycin are available. Trehalose is so safe that it is approved for use as a food; and though rapamycin has substantially greater side effects, it is an FDA approved drug for long term use (for transplant patients).
While treatment with RNAi could potentially decrease levels of mutant protein at the other end by decreasing its production, the technology for this method is not (yet) available, and its risks are unknown.
Comments I heartily applaud the authors' recommendation that trehalose is an important and safe addition to the group of agents that should be tested as a treatment for HD.
Testing will require more animal and human studies to determine adequate dosages for best effect. One challenge is that only a tiny fraction of consumed trehalose reaches brain cells, and drug developers may need to find a way to get more of it to brain to maximize its benefit. And, of course, to find out if trehalose really works in people, clinical trials must be performed. Even if all of this work is done efficiently, it will take a lot of time to complete; years and years of time.
Because time is important for Huntington's people, I think it is a good idea both before and after symptom development to consider using trehalose now. Trehalose is safe. Even small amounts are helpful in cell and animal models of HD. Scientists have shown (in cell and animal models) that it acts at the beginning of the HD cascade as a molecular stabilizer of mutant huntingtin protein [Tanaka M 2004]. Though not as well studied in HD, trehalose probably has significant stabilizing effects on membrane structure and function, as has been shown for membranes that are damaged by many other cell stressors [Elbein AD 2003]. Downstream it acts as an antioxidant and free radical scavenger [Oku K 2005]. It restores calcium homeostasis and improves metabolic parameters in a rat model [Nguyen 2006]. And last, but not least, as shown in the present review, it increases autophagy, accelerating clearance of toxic mutant huntingtin.
Recommendations Start trehalose in small dosages (5 grams) several times a day as part of daily meals. Gradually increase dosage until it causes diarrhea. This can be quite variable from person to person. Though we recommended 25 grams three times a day for HDDW trial participants, a smaller dosage that causes diarrhea probably results in equivalent levels of trehalose reaching the blood stream.
Trehalose is about half as sweet as sugar but contains just as many calories. A 75 gram per day dosage is about 300 calories. If using trehalose, you should use it as a sugar substitute not an addition to sugar. Please see our Trehalose Fact Page for more information. Trehalose can be ordered in bulk from Brooklyn Premium Corporation under the brand name of Neurocoat.
, Max Delbrueck Center, Berlin. Sep 2006. Abstract #48. Proceedings (PDF)
Ravikumar B, Berger Z, Vacher C, O'Kane CJ, Rubinsztein DC. Rapamycin pre-treatment protects against apoptosis. Hum Mol Genet. 2006 Apr 1;15(7):1209-16. Epub 2006 Feb 23. PubMed abstract
Tanaka M, Machida Y, Niu S, Ikeda T, Jana NR, Doi H, Kurosawa M, Nekooki M, Nukina N. Trehalose alleviates polyglutamine-mediated pathology in a mouse model of Huntington disease. Nat Med. 2004 Feb;10(2):148-54. Epub 2004 Jan 18. PubMed abstract
Elbein AD, Pan YT, Pastuszak I, Carroll D. New insights on trehalose: a multifunctional molecule. Glycobiology. 2003 Apr;13(4):17R-27R. Epub 2003 Jan 22. PubMed abstract
Oku K, Kurose M, Kubota M, Fukuda S, Kurimoto M, Tujisaka Y, Okabe A, Sakurai M. Combined NMR and quantum chemical studies on the interaction between trehalose and dienes relevant to the antioxidant function of trehalose. J Phys Chem B. 2005 Feb 24;109(7):3032-40. PubMed abstract
Nguyen HP, Bonin M, Stephan M, Kuhn M, Holzmann C, Reilmann R, von Horsten S, Rieb O. Trehalose treatment restores calcium homeostasis in transgenic rat model of Huntington's disease. Proceedings of Neurodegenerative Diseases: Molecular Mechanisms in a Functional Genomics Framework