Polyglutamiinitaudit

The Channel Hypothesis - Do different degenerative diseases share a common toxic mechanism?

HD Lighthouse Contributing Editor's Comment: In 1997, researchers discovered that the mutant huntingtin protein bunches up to form nuclear inclusions (NIs) in the cells of HD mice [1]. Since that time, Huntington's has been classified as a disease of aberrant protein accumulation. Other diseases in this class include Alzheimer's, Parkinson's, prion (mad-cow) disease, and type II diabetes.

Diagram of beta(β) sheet showing the hydrogen (H) bonding (dashed lines) between protein strands; arrows show the different orientations of the adjacent protein strands (Wikipedia, http://en.wikipedia.org/wiki/Beta_sheet).

However, recent studies have found that the accumulated proteins in these different diseases - the proteins forming NIs, or amyloid or aggregates - have still more in common, namely their shape [2]. This common shape is due to a pattern of molecular hydrogen bonding that forms between strands of the aberrant proteins, producing so-called beta (β) sheets. Beta sheets consist of amino acid sequences that are adjacent and in parallel, in such a way that hydrogen bonds form between the two strands.

It has been known or suspected for some time that HD and other aggregates are rich in this structure known as beta sheets. Linus Pauling and Robert Corey first postulated the existence of beta sheets in 1951 [3], as one basic protein structure. Dr. Max Perutz, the Nobel prize winning father of X-ray crystallography, predicted that polyglutamine strands specifically would zip up due to their hydrogen bonding into a compact structure held together by a polar zipper [4] to form the beta sheets. (Polyglutamine strands are protein pieces that consist of CAG repeats, exactly like the repeats seen in Huntington's; Huntington's is a polyglutamine disease.) While the protein fragments that make up aggregates in the different diseases have different sequences of amino acids, the backbones of these different proteins are identical, and the hydrogen bonding of the backbones (as well as bonding between the amino acid residues) produces the aggregations.

When full-length nuclear inclusions of the huntingtin protein were first discovered in HD mice [1], they were believed to be the critical pathological trigger of the disease - the "smoking gun." However, later research found conflicting evidence about the exact role of these inclusions - for example, a 1999 paper by Kuemmerle and colleagues found that NIs were not associated with neuronal death in HD [5] - and controversy ensued. The consensus today is that it is not the largest inclusions that are most toxic to neurons. Apparently, smaller inclusions of interconnected proteins (oligomers, or mid-sized molecules) represent a mid-stage in the development of the largest inclusions, and these oligomers seem to be a major toxic agent, according to research.

The beta(β) sheet structure for a polyglutamine disease (from M.F. Perutz, T. Johnson, M. Suzuki, and J.T. Finch, Glutamine repeats as polar zippers: their possible role in inherited neurodegenerative diseases, Proceedings of the National Academy of Sciencees USA, 1994, June 7, vol. 91, no.12, pp. 5355-8).

A new paper by Dr. Charles Glabe of the University of California, Irvine, (abstract below) reviews the NI/aggregation/amyloid literature and makes an intriguing case that the common structure of these aggregations may be a disease mechanism that different diseases have in common.

Another important feature of aggregate formation is that it seems to happen reasonably early in disease processes, and, for a variety of diseases, including HD, it may be an upstream event that leads to many downstream toxic cellular processes. More specifically, there is evidence to believe that, once the various amyloid oligomers are formed in the various diseases, they punch holes, or pores, in the cell membrane. This assault in turn may make the cell more permeable, leading to the uncontrolled influx of calcium into the cell, a process that itself may then destabilize many other essential cell processes. The idea that such pore formation leads to many downstream pathological processes is called "the channel hypothesis." Dr. Glabe observes that the increase in intracellular calcium may be the proximate initiator of several pathogenic pathways, including oxidative damage, altered signaling pathways, mitochondrial dysfunction, and cell death.

To the degree Dr. Glabe's hypothesis is true, then modifying the upstream events that lead to channel formation might eliminate many damaging downstream cellular processes in HD and other protein aggregation diseases. That would be great news. Additionally, if the diseases share a common toxic mechanism, that means scientists focusing on these different diseases are actually working on different instances of the same puzzle. If this commonality is borne out in further research, it could speed drug discovery for HD.

We look forward to hearing much more about the channel hypothesis from pharmaceutical companies and academic scientists who will be searching for compounds to prevent channel formation in HD.

References:

1. Davies SW, Turmaine M, Cozens BA, DiFiglia M, Sharp AH, Ross CA, Scherzinger E, Wanker EE, Mangiarini L, Bates GP. Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation. Cell. 1997, Aug 8;90(3):537-48.

2. Kayed R, Head E, Thompson JL, McIntire TM, Milton SC, Cotman CW, Glabe CG. Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis. Science. 2003, Apr 18;300(5618):486-9.

3. Eisenberg, David. The discovery of the a-helix and b-sheet, the principal structural features of proteins. Proceedings of the National Academy of Sciences. 2003, Sept 30;100(20):11207-11210 (http://www.pnas.org/cgi/content/full/100/20/11207).

4. Perutz MF. Polar zippers: their role in human disease. Pharm Acta Helv. 1995, Mar;69(4):213-24.

5. Kuemmerle, S, Gutekunst, CA, Klein, AM, Li XJ, Li SH, Beal, MF, Hersch, SM, Ferrante, RJ. Huntington aggregates may not predict neuronal death in Huntington's disease. Ann Neurol. 1999, Dec;46(6):842-9.

Commentary by Malcolm Casale, Ph.D. and Ann Covalt, M.A.
Posted to the HDL: 09 Mar 2006