Protein Conformational Pathology in Alzheimers and Other Neurodegenerative Diseases; New Targets for Therapy

E.      Zerovnik

doi:10.2174/156720510790274437

Abstract

The whole set of the so-called ‹ conformational› disorders, among them systemic amyloidoses, various dementias and other neurodegenerative diseases such as Parkinsons, Alzheimers and amyotropic lateral sclerosis, may have similar molecular backgrounds: changes in protein conformation and aggregation, which lead to toxic amyloid oligomers and fibrils. The so called aggresomes in eukaryotes (equivalent to inclusion bodies in prokaryotes), located at the centriole by the nucleus and composed of aggregated proteins, are believed to sequester the toxic material. They eventually get cleared from the cell by autophagy. When the cell defense system fails due to continuous production of a mutated protein or to other damage to the cell, such as oxidative stress or protein modification as part of normal aging, familial or sporadic neurodegenerative diseases develop. Initially - for years - they are silent with no or mild symptoms. It could well be that aggregates represent a response to some other trigger or even a means of defense. However, the inherited cases with mutations leading to increased aggregation suggest the opposite to be the case. Evidence has accumulated that the soluble oligomers of amyloidogenic proteins are themselves cytotoxic and trigger a cascade of detrimental events in the cell, as summarized in the “amyloid cascade hypothesis”. Among other plausible hypotheses for the mechanism of toxicity is the “channel hypothesis”, which states that the soluble oligomers interact with cell membranes, causing influx of Ca2+ ions, which is an early sign of pathology and contributes to uncontrolled neurotransmission. Another factor are metal ions, such as Zn2+, Cu2+, Fe3+, Al3+, etc., leading to the “metal hypothesis”. The delicate balance of metal ions in the brain is important to prevent oxidative stress, which can itself modify proteins and make them aggregation-prone. The advances in molecular and cellular studies will hopefully lead to novel therapies and eventually to a cure.

Keywords: AD, protein conformation, protein aggregation, aggresome, prefibrillar oligomers, amyloid toxicity, amyloid fibrils, channel hypothesis, metal hypothesis, chaperones