- Proteopathy
Proteopathy (Proteo- ["pref". protein] ; -pathy ["suff". disease] ; proteopathies "pl".; proteopathic "adj".) is the abnormal accumulation and toxicity of
proteins in certain disease states.cite journal | author = Walker LC and LeVine H | title = The cerebral proteopathies | journal = Neurobiol Aging | volume = 21 | pages = 559–561 | year = 2000 | pmid = 10924770 | doi = 10.1016/S0197-4580(00)00160-3 ] The proteopathies (sometimes referred to as "proteinopathies") comprise more than 30 diseases that affect a variety of organs and tissues, includingAlzheimer's disease ,Parkinson's disease ,type 2 diabetes ,amyloidosis , selective hyperproteolytic diseases (e.g. critical illness myopathies or tumor cachexia), and a wide range of other disorders (see Table).cite journal | author=Walker LC, LeVine III H | title = The cerebral proteopathies: Neurodegenerative disorders of protein conformation and assembly | journal = Mol Neurobiol | volume = 21 | pages = 83–95 | year = 2000 | pmid = 11327151 | doi = 10.1385/MN:21:1-2:083] cite journal | author = Chiti F, Dobson CM | title = Protein misfolding, functional amyloid, and human disease | journal = Ann Rev Biochem | volume = 75 | pages = 333–366 | year = 2006 | pmid = 16756495 | doi = 10.1146/annurev.biochem.75.101304.123901 ] cite journal | author = Friedrich O | title = Critical illness myopathy: what is happening? | journal = Curr Opin Clin Nutr Metab Care | volume = 9 | pages = 403–409 | year = 2006 | pmid = 16778569] cite journal | author = Spinner NB | title = CADASIL: Notch signaling defect or protein accumulation problem? | journal = J Clin Invest | volume = 105 | pages = 561–562 | year = 2000 | pmid = 10712425 | doi = 10.1172/JCI9511] cite journal | author = Carrell RW, Lomas DA | title = Conformational disease | journal = Lancet | volume = 350 | pages = 134–138 | year = 1997 | pmid = 9228977 | doi = 10.1016/S0140-6736(97)02073-4] cite journal | author = Westermark P et al. | title = A primer of amyloid nomenclature | journal = Amyloid | volume = 14 | pages = 179–183 | year = 2007 | pmid = 16076605 | doi = 10.1080/13506120701460923]The proteopathies also are called "protein conformational diseases",cite journal | author = Carrell RW, Lomas DA | title = Conformational disease | journal = Lancet | volume = 350 | pages = 134–138 | year = 1997 | pmid = 9228977 | doi = 10.1016/S0140-6736(97)02073-4 ] because a change in the 3-dimensional folding (conformation) of a protein increases the tendency of the protein to misfold and polymerize into aggregates that are resistant to clearance, and can become pathogenic. Because of the common structure of the
polypeptide backbone, all proteins have the potential to misfold under some conditions.cite journal | author = Dobson CM | title = Protein misfolding, evolution and disease | journal = TIBS | volume = 24 | pages = 329–332 | year = 1999 | pmid = 10470028 ]Only certain proteins are linked to proteopathy, possibly due to instability or other structural features of the monomeric protein that increase the probability of misconformation,cite journal | author = Carrell RW, Lomas DA | title = Conformational disease | journal = Lancet | volume = 350 | pages = 134–138 | year = 1997 | pmid = 9228977 | doi = 10.1016/S0140-6736(97)02073-4 ] cite journal | author = Dobson CM | title = Protein misfolding, evolution and disease | journal = TIBS | volume = 24 | pages = 329–332 | year = 1999 | pmid = 10470028 ] which in nearly all instances involves an increase in
beta-sheet secondary structure.cite journal | author = Dobson CM | title = Protein misfolding, evolution and disease | journal = TIBS | volume = 24 | pages = 329–332 | year = 1999 | pmid = 10470028 ] cite journal | author = Carrell RW, Lomas DA | title = Conformational disease | journal = Lancet | volume = 350 | pages = 134–138 | year = 1997 | pmid = 9228977 | doi = 10.1016/S0140-6736(97)02073-4 ] cite journal | author = Selkoe DJ | title = Folding proteins in fatal ways | journal = Nature | volume = 426 | pages = 900–904 | year = 2003 pmid = 14685251 | doi = 10.1038/nature02264] Potential risk factors for proteopathic diseases augment the tendency of vulnerable proteins to self-assemble. They include destabilizing changes in the primaryamino acid sequence of the protein,post-translational modifications (such ashyperphosphorylation ), changes in temperature or pH, an increase in production of a protein, or a decrease in its clearance.cite journal | author = Carrell RW, Lomas DA | title = Conformational disease | journal = Lancet | volume = 350 | pages = 134–138 | year = 1997 | pmid = 9228977 | doi = 10.1016/S0140-6736(97)02073-4 ] cite journal | author = Dobson CM | title = Protein misfolding, evolution and disease | journal = TIBS | volume = 24 | pages = 329–332 | year = 1999 | pmid = 10470028 ] cite journal | author = Walker LC and LeVine H | title = The cerebral proteopathies | journal = Neurobiol Aging | volume = 21 | pages = 559–561 | year = 2000 | pmid = 10924770 | doi = 10.1016/S0197-4580(00)00160-3 ] Advancing age frequently is a risk factor.cite journal | author = Walker LC and LeVine H | title = The cerebral proteopathies | journal = Neurobiol Aging | volume = 21 | pages = 559–561 | year = 2000 | pmid = 10924770 | doi = 10.1016/S0197-4580(00)00160-3 ]In some proteopathies, abnormal assembly can be templated on an exogenous protein, typically a misfolded form of the same protein.cite journal | author = Hardy J | title = Expression of normal sequence pathogenic proteins for neurodegenerative disease contributes to disease risk: 'permissive templating' as a general mechanism underlying neurodegeneration | journal = Biochem Soc Trans | volume = 33 | pages = 578–581 | year = 2005 | pmid = 16042548 | doi = 10.1042/BST0330578] cite journal | author = Walker LC, LeVine H, Mattson MP, Jucker M | title = Inducible proteopathies | journal = TINS | volume = 29 | pages = 438–443 | year = 2006 | pmid = 16806508] In this way, the disease state can be induced in a susceptible host by the introduction of diseased tissue extract from an afflicted donor. The best known form of such infectious (or transmissible) proteopathy is
prion disease , which can be transmitted by exposure of a host organism to purified prion protein in a disease-causing conformation.cite journal | author = Prusiner SB | title = Shattuck lecture—Neurodegenerative diseases and prions | journal = N Engl J Med | volume = 344 | pages = 1516–1526 | year = 2001 | pmid = 11357156 | doi = 10.1056/NEJM200105173442006] cite journal | author = Zou WQ, Gambetti P | title = From microbes to prions: the final proof of the prion hypothesis | journal = Cell | volume = 121 | pages = 155–157 | year = 2005 | pmid = 15851020 | doi = 10.1016/j.cell.2005.04.002] There is now evidence that other proteopathies are inducible by a similar mechanism, including AA amyloidosis, apolipoprotein AII amyloidosis, andAβ amyloidosis.cite journal | author = Walker LC, LeVine H, Mattson MP, Jucker M | title = Inducible proteopathies | journal = TINS | volume = 29 | pages = 438–443 | year = 2006 | pmid = 16806508] cite journal | author = Meyer-Luehmann M, et al. | title = Exogenous induction of cerebral β-amyloidogenesis is governed by agent and host | journal = Science | volume = 313 | pages = 1781–1784 | year = 2006 | pmid = 16990547 | doi = 10.1126/science.1131864 ] In all of these instances, an aberrant form of the protein itself appears to be the pathogenic agent.References
External links
* [http://www.emedicine.com/med/topic3377.htm Amyloidosis]
* [http://www.emedicine.com/neuro/topic662.htm Prion-Related Diseases]
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