Synuclein and Amyloid Diseases

NSAIDs, such as ibuprofen and aspirin are possible treatments to inhibit the aggregation of proteins (synuclein, beta amyloid) on charged polymers in amyloid diseases, such as Parkinson’s disease, Alzheimer’s disease, etc. Contradictory studies show that intracellular aggregate formation may be protective, since dimers are more toxic than aggregates.

The list of amyloid diseases is long and there are few effective treatments. In each case a protein starts to accumulate in fibers that form amyloid plaques inside or outside the cells. The large aggregates outside are toxic. Inside it appears that the large aggregates are not as toxic as small clumps, oligomers, of the protein.

The amyloid proteins are stacked up in the fibers in a very organized way, so that the same portions of the protein are lined up on each side of the fibers. Outside the cell, the regions with basic amino acids interact with heparin, and in Alzheimer’s disease, for example, the beta amyloid plaque is half heparin. In test tube experiments, fiber formation from protein solutions is accelerated by adding heparin.

Amyloid fibers also form inside cells in the case of the tau fibers of Alzheimer’s disease or the synuclein aggregates in Parkinson’s disease. In theses cases, there should not be any intracellular heparin, and it is not known what polyanion (RNA?) serves to accelerate fiber formation in these cases.

Non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen and aspirin, reduce the incidence of Parkinson’s and Alzheimer’s diseases. It has recently been shown that in test tube experiments, NSAIDs also decrease the formation of amyloid fibers from synuclein.

Amyloid fibers can be stained by Congo Red and thioflavin. Curcumin is the active component of tumeric and it has a structure related to Congo Red. Curcumin has been shown in recent studies to block synuclein amyloid formation.

In addition, the heparin in the fiber complexes can be stained with berberine. Berberine is a traditional herbal treatment for arthritis. It would not be surprising if it was also effective against Alzheimer’s amyloid plaque.

The large extracellular plaque aggregates appear to be toxic, but the small, oligomeric aggregate of protein appear to be the toxic form in cells. Recent experiments show that facilitating the formation of large intracellular aggregates minimizes the toxicity in animal models of Huntington’s and Parkinson’s diseases. It appears that the large visible aggregates are not the form that kills the cell.

For the time being, the only safe treatments that focus on amyloid fiber formation are the NSAIDs, curcumin and perhaps berberine.

references:
Hirohata M, Ono K, Morinaga A, Yamada M. 2008. Non-steroidal anti-inflammatory drugs have potent anti-fibrillogenic and fibril-destabilizing effects for alpha-synuclein fibrils in vitro. Neuropharmacology 54(3):620-7.

Pandey N, Strider J, Nolan WC, Yan SX, Galvin JE. 2008. Curcumin inhibits aggregation of alpha-synuclein. Acta Neuropathol. 115(4):479-89.

Bodner RA, Outeiro TF, Altmann S, Maxwell MM, Cho SH, Hyman BT, McLean PJ, Young AB, Housman DE, Kazantsev AG. 2006. Pharmacological promotion of inclusion formation: a therapeutic approach for Huntington's and Parkinson's diseases. Proc Natl Acad Sci U S A. 103(11):4246-51.

Outeiro TF, Kontopoulos E, Altmann SM, Kufareva I, Strathearn KE, Amore AM, Volk CB, Maxwell MM, Rochet JC, McLean PJ, Young AB, Abagyan R, Feany MB, Hyman BT, Kazantsev AG. 2007. Sirtuin 2 inhibitors rescue alpha-synuclein-mediated toxicity in models of Parkinson's disease. Science. 317(5837):516-9.