The Durk Pearson & Sandy Shaw®
Life Extension NewsTM
Volume 17 No. 1 • January 2014


Natural Sugar and Osmolyte Trehalose
May Be a Novel Treatment for Parkinson’s—
AND IS SAFE AND INEXPENSIVE

Trehalose is a natural sugar1 that acts as an osmolyte by preventing abnormal protein folding in the endoplasmic reticulum of cells, the special organelle where proteins are synthesized and folded. Trehalose guides proteins into their proper shape by preventing water from interacting with the protein surface in the process of folding,2 which would interfere with the complex interactions of the hydrophobic (water avoiding) and hydrophilic (water attracted) parts of the protein from interacting properly (imagine a protein molecule as a complex origami sculpture with lots of moving parts). We take trehalose as a daily supplement in a mixture of several osmolytes for helping proteins fold properly, as the aggregation of improperly folded proteins occurs as part of the aging process. Several serious diseases, such as Parkinson’s and Alzheimer’s disease, are associated with improperly folded, aggregated proteins. In the case of Parkinson’s, the aggregated protein is alpha-synuclein.

Trehalose has been reported in recent publications to inhibit protein aggregation that occurs in Alzheimer’s disease, Huntington’s disease,3 and prion disease. The second page of a recent paper4 shows the molecular structure of trehalose, with its large numbers of hydroxyl groups hanging off the trehalose ring structure. These hydroxyl groups are able to bind and control the movement of parts of complex molecules with large numbers of hydrogen bonds (as found in proteins). Thus, trehalose is made to order as a tool for controlling the folding of proteins.

The researchers tested trehalose on the formation of mature A53T AS (alpha synuclein) protofibrils (a form of AS folding that may be neurotoxic for dopaminergic neurons, the type of neurons that are dysfunctional in Parkinson’s disease). The data showed that “trehalose at high concentration could slow down the formation of beta-sheet aggregates during the early period of incubation, stabilize and increase the partially-folded oligomers or beta-sheet-rich protofilaments which increase the ThT fluorescence intensity [the instrumental measure of beta-sheet aggregates], and prevent the formation of the mature A53T AS fibrils during the late period of incubation.”4

As the authors explain, there are three hypotheses for how trehalose stabilizes protein folding: water-layer with preferential exclusion, water-replacement, and mechanical-entrapment. The authors discuss how these hypotheses may explain, at least in part, the results they observed.

The researchers suggest that a better understanding of the neurotoxicity of the various species of aggregated AS will be “crucial” for understanding how to use trehalose for best results. In the meantime, they report that trehalose has been reported in other research to enhance autophagy (a process akin to self-eating whereby unneeded or toxic cellular debris is disposed of)5 and to have anti-inflammatory effects; both of these effects are beneficial in Parkinson’s disease.4 Trehalose has also been shown to increase lifespan in the nematode Caenorhabditis elegans.4

References

  1. For example, mushrooms contain up to 10–25% trehalose by dry weight. See Higashiyama. Novel functions and applications of trehalose. Pure Appl Chem. 74(7):1263-69 (2002).
  2. Street et al. A molecular mechanism for osmolyte-induced protein stability. Proc Natl Acad Sci USA. 103(38):13997-14002 (2006).
  3. Tanaka et al. Trehalose alleviates polyglutamine-mediated pathology in a mouse model of Huntington disease. Nat Med. 10(2):148-54 (2004).
  4. Yu et al. Trehalose inhibits fibrillation of A53T mutant alpha-synuclein and disaggregates existing fibrils. Arch Biochem Biophys. 523:144-50 (2012).
  5. Sarkar et al. Trehalose, a novel mTOR-independent autophagy enhancer, accelerates the clearance of mutant Huntingtin and alpha synuclein. J Biol Chem. 282(8):5641-52 (2007).

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