Abstract:
:There is increasing recognition that numerous neurodegenerative conditions have the same underlying pathogenetic mechanism, namely a change in protein conformation, where the beta-sheet content is increased. In Alzheimer's disease, amyloid deposition in the form of neuritic plaques and congophilic angiopathy is driven by the conversion of normal soluble amyloid-beta peptide (sA beta) to A beta plaques; while in the prionoses the critical event is the conversion of normal prion protein, PrP(C), to the disease-associated form, PrP(Sc). This common theme in the pathogenesis of these disorders and the extracellular localization of the accumulating abnormal protein make them highly amenable to therapeutic approaches based on experimental manipulation of protein conformation and clearance. A number of different approaches under current development include drugs which affect the processing of the precursor proteins drugs the clearance of the amyloidogenic protein, and which inhibit or prevent the conformation change and immunological approaches. Particularly interesting are compounds termed 'beta-sheet breakers' that directly target the abnormal conformational change both for A beta- and PrP(Sc)-related deposits. In addition, immune system activation can serve as beta-sheet breakers and/or to increase the clearance of the disease-associated proteins. These conformation-based approaches appear to hold the best promise for therapies for this devastating group of disorders.
journal_name
Biochem Soc Transjournal_title
Biochemical Society transactionsauthors
Wisniewski T,Brown DR,Sigurdsson EMdoi
10.1042/bst0300574keywords:
subject
Has Abstractpub_date
2002-08-01 00:00:00pages
574-8issue
4eissn
0300-5127issn
1470-8752journal_volume
30pub_type
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