The Durk Pearson & Sandy Shaw®
Life Extension NewsTM
Volume 13 No. 5 • October 2010


Protein Aggregation in Neurodegenerative Diseases

Protection by Trehalose Against Mutant Protein
Causing a Neurodegenerative Disease

As we have written before (see “The Origami of Aging” in the September 2008 issue), trehalose is a natural disaccharide (sugar) found in many plants, bacteria, yeast, fungi (mushrooms can contain up to 10-25% trehalose by dry weight*), insects, and invertebrates but not in mammals1 that acts as an osmolyte, a type of chaperone that helps proteins to fold properly. “Trehalose has also been shown to inhibit the aggregation of disease-related proteins, including polyglutamine- expanded huntingtin in Huntington disease, beta-amyloid in Alzheimer disease, and protease-resistant prion protein in prion disease.” 1 Trehalose has been reported to improve motor dysfunction in a mouse model of Huntington disease. 1b


* Higashiyama. Novel functions and applications of trehalose. Pure Appl Chem 74(7):1263-1269 (2002).


Osmolytes such as trehalose can help protect against the improper protein folding2,3 (and accompanying protein dysfunction) that occurs with increasing frequency with aging. We report here further evidence of the protective effects of trehalose in another neurodegenerative disease, spinocerebellar ataxia type 14 (SCA14), which is associated with genetic mutations such as CAG trinucleotide repeats (the type of mutation found in Huntington disease) in the gene for protein kinase Cgamma.

Though SCA14 is an uncommon disorder, the importance of preventing improper protein folding applies broadly to many different proteins. Hence, we were delighted to see this new research with trehalose. As the authors1 state: “we believe that drugs that inhibit the aggregation of mutant gammaPKC might be useful to treat SCA14 and related neurodegenerative diseases.” (Trehalose is a natural product, however, not a drug. It is the FDA that has decided that anything that can be used to treat a disease is a drug even if they are natural products available as dietary supplements or as components of foods. As the fact that dietary supplements or foods can be used to treat some diseases is “forbidden knowledge,” no one selling dietary supplements or foods can communicate this information to the public without risking a big fine or even prison. (Notice how this is analogous to earlier attempts by organized religion to monopolize the content of their holy books by prohibiting their being published in anything but Latin, which could only be understood by priests certified by the Church. This stuff doesn’t go away, folks, it just gets continually resurrected to be administered by bureaucracies with new names and updated punishments.)

Anyway, getting back to trehalose ... The authors show that trehalose reduced the aggregation of the mutant gammaPKC, “thereby inhibiting the apoptotic cell death in SH-SY5Y cells and primary cultured Purkinje cells.” Trehalose was found to act by directly stabilizing the conformation of mutant gammaPKC without affecting protein turnover.

The authors conclude that “[t]rehalose is widely used in foods as a sweetener and in cosmetics as a humectant; thus its safety has already been established. We expect that trehalose has the potential to become a useful drug for treatment of neurodegenerative diseases, including SCA14.”

We have included trehalose in our osmolyte formulation to help proteins fold properly. Each tablespoon (1 serving) of this formulation contains 1000 mg of trehalose plus 500 mg to 1500 mg of each of 7 other osmolytes (betaine, creatine monohydrate, glycine, inositol, L-proline, taurine, and beta alanine).

References

1. Seki et al. Effect of trehalose on the properties of mutant gammaPKC, which causes spinocerebellar ataxia type 14, in neuronal cell lines and cultured Purkinje cells. J Biol Chem 285(43):33252-33264 (2010).
1b. Tanaka et al. Trehalose alleviates polyglutamine-mediated pathology in a mouse model of Huntington disease. Nat Med 10(2):148-154 (2004).
2. Street et al. A molecular mechanism for osmolyte-induced protein stability. Proc Natl Acad Sci USA 103(38):13997- 14002 (2006)
3. Yancey. Organic osmolytes as compatible, metabolic and counteracting cytoprotectants in high osmolarity and other stresses. J Exp Biol 208:2819-2830 (2005).

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