3 results
15 - Neurodegenerative diseases
- from PART II - DISORDERS OF HIGHER FUNCTION
-
- By Stanley B. Prusiner, Institute for Neurodegenerative Diseases and Departments of Neurology
- Edited by Arthur K. Asbury, University of Pennsylvania School of Medicine, Guy M. McKhann, The Johns Hopkins University School of Medicine, W. Ian McDonald, University College London, Peter J. Goadsby, University College London, Justin C. McArthur, The Johns Hopkins University School of Medicine
-
- Book:
- Diseases of the Nervous System
- Published online:
- 05 August 2016
- Print publication:
- 11 November 2002, pp 210-236
-
- Chapter
- Export citation
-
Summary
Twenty-five years ago, there was little understanding of the causes of neurodegeneration. In fact, the term degenerative disease was used as a wastebasket for illnesses of unknown etiology. But progress over the past quarter of a century in research focused on degenerative disorders of the central nervous system (CNS) has been impressive. It is now clear that neurodegenerative diseases are caused by the misprocessing of proteins. In each disease, one or more specific proteins have been identified that are misprocessed; this results in the accumulation of one or more particular proteins.
The proteins that accumulate in the CNS of patients with neurodegenerative diseases were initially identified by purifying these polypeptides from the brains of animals or humans with these diseases (Glenner & Wong, 1984; Masters et al., 1985; Prusiner et al., 1982). Subsequently, molecular genetics was used to identify the genes responsible for the familial forms of Alzheimer's and Parkinson's diseases as well as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Similarly, molecular genetic investigations of Huntington's disease (HD) and the spinocerebellar ataxias have led to the identification of the genes responsible for the pathogenesis of these illnesses.
Of all the studies on neurodegenerative diseases, the discovery of prions has been most unexpected. The finding that a protein can act as an infectious pathogen and cause degeneration of the CNS was unprecedented (Prusiner, 1998b). The prion concept was so novel that achieving acceptance required a long and arduous battle (Prusiner, 1999). The prion concept not only explained how a disease can be both infectious and genetic, but it has also created new disease paradigms and revolutionized thinking in biology.
Although progress in the study of neurodegeneration has been impressive, there are still no curative treatments.Only for patients with Parkinson's disease is there a palliative drug with reasonable efficacy (Cotzias et al., 1967). L-dopa and related drugs do not stop the underlying degeneration, which often renders patients refractory to pharmacologic treatment in the later stages of Parkinson's disease (Marsden & Parkes, 1977). Stereotactic surgery has produced limited success in ameliorating the symptoms of Parkinson's disease when L-dopa becomes ineffective. Transplantation of cells secreting dopamine into the brains of patients with advanced Parkinson's disease is the subject of much research. It is noteworthy that many patients with Parkinson's disease develop dementia in the later stages of this disorder.
The prion domain of yeast Ure2p induces autocatalytic formation of amyloid fibers by a recombinant fusion protein
- MARTIN SCHLUMPBERGER, HOLGER WILLE, MICHAEL A. BALDWIN, DAREL A. BUTLER, IRA HERSKOWITZ, STANLEY B. PRUSINER
-
- Journal:
- Protein Science / Volume 9 / Issue 3 / March 2000
- Published online by Cambridge University Press:
- 01 March 2000, pp. 440-451
- Print publication:
- March 2000
-
- Article
- Export citation
-
The Ure2 protein from Saccharomyces cerevisiae has been proposed to undergo a prion-like autocatalytic conformational change, which leads to inactivation of the protein, thereby generating the [URE3] phenotype. The first 65 amino acids, which are dispensable for the cellular function of Ure2p in nitrogen metabolism, are necessary and sufficient for [URE3] (Masison & Wickner, 1995), leading to designation of this domain as the Ure2 prion domain (UPD). We expressed both UPD and Ure2 as glutathione-S-transferase (GST) fusion proteins in Escherichia coli and observed both to be initially soluble. Upon cleavage of GST-UPD by thrombin, the released UPD formed ordered fibrils that displayed amyloid-like characteristics, such as Congo red dye binding and green-gold birefringence. The fibrils exhibited high β-sheet content by Fourier transform infrared spectroscopy. Fiber formation proceeded in an autocatalytic manner. In contrast, the released, full-length Ure2p formed mostly amorphous aggregates; a small amount polymerized into fibrils of uniform size and morphology. Aggregation of Ure2p could be seeded by UPD fibrils. Our results provide biochemical support for the proposal that the [URE3] state is caused by a self-propagating inactive form of Ure2p. We also found that the uncleaved GST-UPD fusion protein could polymerize into amyloid fibrils by a strictly autocatalytic mechanism, forcing the GST moiety of the protein to adopt a new, β-sheet-rich conformation. The findings on the GST-UPD fusion protein indicate that the ability of the prion domain to mediate a prion-like conversion process is not specific for or limited to the Ure2p.
Copper binding to octarepeat peptides of the prion protein monitored by mass spectrometry
- RANDY M. WHITTAL, HAYDN L. BALL, FRED E. COHEN, ALMA L. BURLINGAME, STANLEY B. PRUSINER, MICHAEL A. BALDWIN
-
- Journal:
- Protein Science / Volume 9 / Issue 2 / February 2000
- Published online by Cambridge University Press:
- 01 February 2000, pp. 332-343
- Print publication:
- February 2000
-
- Article
- Export citation
-
Electrospray ionization mass spectrometry (ESI-MS) was used to measure the binding of Cu2+ ions to synthetic peptides corresponding to sections of the sequence of the mature prion protein (PrP). ESI-MS demonstrates that Cu2+ is unique among divalent metal ions in binding to PrP and defines the location of the major Cu2+ binding site as the octarepeat region in the N-terminal domain, containing multiple copies of the repeat ProHisGlyGlyGlyTrpGlyGln. The stoichiometries of the complexes measured directly by ESI-MS are pH dependent: a peptide containing four octarepeats chelates two Cu2+ ions at pH 6 but four at pH 7.4. At the higher pH, the binding of multiple Cu2+ ions occurs with a high degree of cooperativity for peptides C-terminally extended to incorporate a fifth histidine. Dissociation constants for each Cu2+ ion binding to the octarepeat peptides, reported here for the first time, are mostly in the low micromolar range; for the addition of the third and fourth Cu2+ ions to the extended peptides at pH 7.4, KD's are <100 nM. N-terminal acetylation of the peptides caused some reduction in the stoichiometry of binding at both pH's. Cu2+ also binds to a peptide corresponding to the extreme N-terminus of PrP that precedes the octarepeats, arguing that this region of the sequence may also make a contribution to the Cu2+ complexation. Although the structure of the four-octarepeat peptide is not affected by pH changes in the absence of Cu2+, as judged by circular dichroism, Cu2+ binding induces a modest change at pH 6 and a major structural perturbation at pH 7.4. It is possible that PrP functions as a Cu2+ transporter by binding Cu2+ ions from the extracellular medium under physiologic conditions and then releasing some or all of this metal upon exposure to acidic pH in endosomes or secondary lysosomes.
![](/core/cambridge-core/public/images/lazy-loader.gif)