Why is Trehalose Important?

• Trehalose has a very important property that helps it to stabilize proteins and can thus be used as a biological preservative.
• It is this very feature that may useful for treating Huntington’s disease, as well as other neurodegenerative diseases.  

How Does Trehalose Work in Huntington's Disease (HD) or Chorea?

• A protein is made up of a string of amino acids. As the amino acids are strung together, the protein begins to fold up on itself until it gets to its final three-dimensional (3D) shape.
• Normal, stable proteins have no problem maintaining their shapes and functions in the cell. However, the huntingtin proteins  are not very stable on their own, so they form into clumps known as protein aggregates.
  
• Scientists think that if these proteins can be stabilized before they are fully folded, the protein aggregations will not form. One research group set out to test just that idea.
• They found that disaccharides are good at stabilizing molecules with extra CAG repeats, and are therefore capable of preventing protein aggregation. Trehalose was the most effective stabilizer of all the disaccharides tested.
• The researchers think that Trehalose works by binding directly to the glutamine repeat section (the extra part of the protein that usually makes it unstable), while leaving the normal proteins unaffected.

Tanaka, M., Y. Machida, S. Niu, T. Ikeda, N. R. Jana, H. Doi, M. Kurosawa, M. Nekooki and N. Nukina (2004). "Trehalose alleviates polyglutamine-mediated pathology in a mouse model of Huntington disease." Nat Med 10(2): 148-54. 

• Similar protein aggregations are found in Parkinson's Disease, and there have been positive results using Trehalose in these Parkinson patients.

Oculopharyngeal Muscular Dystrophy

• Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant disease that presents in the fifth or sixth decade of life with dysphagia (difficulty swallowing), ptosis (drooping eyelids) and proximal limb weakness.
• It is caused by an abnormal expansion of a polyalanine tract within the coding region of poly-A binding protein nuclear 1 (PAßPN1).
• This mutant protein demonstrates cellular pathology similar to Huntington’s in that it forms aggregates.
• In OPMD, the culprit mutant protein forms aggregates in nuclei of skeletal muscle fibers, causing injury which culminates in cell dysfunction and death.
  
• Trehalose has been found beneficial in transgenic model systems for this disease.  Trehalose reduces aggregate formation and prolongs viability in the cell model of this disease, and that it delays onset, ameliorates symptoms, and prolongs life in the mouse model of this disease.

Trehalose and Alzheimer's Disease

• Sporadic Alzheimer’s disease is pathologically characterized by aggregation of small beta-amyloid (Aß) peptides into amyloid plaques and neurofibrillary tangles.
• As in other <b>proteinopathy neurodegenerative disease, Alzheimer’s progression is correlated with increasing aggregate load of amyloid, though toxicity is increasingly linked to the formation of oligomeric forms of Aß peptides.¹
  
• Trehalose was studied in vitro, and in cell models of Alzheimer’s by using the proteins beta-amyloid 40 and 42, which are the proteins most prominently implicated in Alzheimer’s.²
• Although Aß40 is the most prominent peptide (10:1), Aß42 is more toxic.
  
• In Vitro Aggregation Formation Studies; Aß40 In vitro: In solution at physiologic concentration, Aß40, incubated alone, displays a time dependent increase in spontaneous aggregation. Co-incubation with trehalose inhibits aggregation of this peptide in a dose-dependent manner. High concentration trehalose completely inhibited aggregation of this peptide.
  
• Aß42: In vitro: In physiologic concentrations, Aß42, when incubated alone aggregates more quickly than Aß40. Aß42 has an additional two hydrophobic amino acids, making this peptide more aggregate prone than Aß40. While trehalose inhibited aggregation of Aß42 in a dose-dependent manner, it was significantly less efficient than the corresponding Aß40. High dose trehalose prevented only 50% aggregation of this more toxic peptide.

1. Walsh, D. M., I. Klyubin, G. M. Shankar, M. Townsend, J. V. Fadeeva, V. Betts, M. B. Podlisny, J. P. Cleary, K. H. Ashe, M. J. Rowan and D. J. Selkoe (2005). "The role of cell-derived oligomers of Abeta in Alzheimer's disease and avenues for therapeutic intervention." Biochem Soc Trans 33(Pt 5): 1087-90.

2. Liu, R., H. Barkhordarian, S. Emadi, C. B. Park and M. R. Sierks (2005). "Trehalose differentially inhibits aggregation and neurotoxicity of beta-amyloid 40 and 42." Neurobiol Dis 20(1): 74-81.

Trehalose and Infection

• Bacterial infections are lethal complications of neutropenia (low white cell count), and antibiotics alone are inadequate therapy for these infections.
• Irradiated mice become severely neutropenic and remain susceptible to infection for 2 to 3 weeks, depending on the dose and quality of radiation.
• In a recent study, it was determined that if the cell wall glycolipid trehalose dimycolate (TDM), derived from Mycobacterium phlei, or a synthetic preparation of TDM was able to (i) enhance survival in mice when given before or after lethal doses of 60Co radiation and (ii) increase nonspecific resistance to postirradiation infection.
• These results indicate that in irradiated mice, TDM can be used to enhance survival and, as a potent stimulant of nonspecific resistance to infection in neutropenic mice, can act synergistically with antibiotic therapy to reduce sepsis and mortality.
• The implications are that with patients about to undergo radiation therapy, the addition of Trehalose may help to keep these patients from becoming septic when they have low white blood cell counts.
   

Infect Immun. 1989 August; 57(8): 2495-2501.