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Proteopathy


Proteopathy (Proteo- [pref. protein]; -pathy [suff. disease]; proteopathies pl.; proteopathic adj.). Proteopathy is the abnormal accumulation and toxicity of proteins in certain disease states.[1] Also, selective hyperproteolytic diseases have been referred to this category, e.g. critical illness myopathies or tumor cachexia.[2] The proteopathies comprise at least 30 diseases that affect a variety of organs and tissues, including Alzheimer's disease, Parkinson's disease, type 2 diabetes, amyloidosis, and a wide range of other disorders (see Table).[3][4]

The proteopathies are also called protein conformational diseases,[5] 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.[6]

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, which in nearly all instances involves an increase in beta-sheet secondary structure. Potential risk factors for proteopathic diseases augment the tendency of vulnerable proteins to self-assemble. They include destabilizing changes in the primary amino acid sequence of the protein, post-translational modifications (such as hyperphosphorylation), changes in temperature or pH, an increase in production of a protein, or a decrease in its clearance. Advancing age frequently is a risk factor.

In some proteopathies, abnormal assembly can be templated on an exogenous protein, typically a misfolded form of the same protein. 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.[7][8] There is now evidence that other proteopathies are inducible by a similar mechanism, including AA amyloidosis, apolipoprotein AII amyloidosis, and amyloidosis.[9][10] In all of these instances, an aberrant form of the protein itself appears to be the pathogenic agent.

Proteopathy Major aggregating protein
Alzheimer's disease, Cerebral β-amyloid angiopathy Amyloid β peptide (Aβ) (senile plaques), Tau protein (fibers)
Prion diseases (multiple) Prion protein
Parkinson's disease and other synucleinopathies (multiple) α-Synuclein
Tauopathies (multiple) Microtubule-associated protein tau
Frontotemporal lobar degeneration (FTLD) (Ubi+, Tau-) TDP-43
Amyotrophic lateral sclerosis (ALS) Superoxide dismutase, TDP-43
Huntington's disease and other triplet repeat disorders (multiple) Proteins with tandem glutamine expansions
Familial British dementia ABri
Familial Danish dementia ADan
Familial encephalopathy with neuroserpin inclusion bodies (FENIB) Neuroserpin
Hereditary cerebral hemorrhage with amyloidosis (Icelandic) (HCHWA-I) Cystatin C
Familial amyloidotic neuropathy, Senile systemic amyloidosis Transthyretin
AL (light chain) amyloidosis (primary systemic amyloidosis) Monoclonal immunoglobulin light chains
AH (heavy chain) amyloidosis Immunoglobulin heavy chains
AA (secondary) amyloidosis Amyloid A protein
Type II diabetes Islet amyloid polypeptide (IAPP; amylin)
Aortic medial amyloidosis Medin (lactadherin)
ApoAI amyloidosis Apolipoprotein AI
ApoAII amyloidosis Apolipoprotein AII
ApoAIV amyloidosis Apolipoprotein AIV
Finnish hereditary amyloidosis Gelsolin
Lysozyme amyloidosis Lysozyme
Fibrinogen amyloidosis Fibrinogen
Dialysis amyloidosis β2-microglobulin
Inclusion body myopathy/myositis Amyloid β peptide (Aβ)
Cataracts Crystallins
Medullary thyroid carcinoma Calcitonin
Cardiac atrial amyloidosis Atrial natriuretic factor
Pituitary prolactinoma Prolactin
Hereditary lattice corneal dystrophy Keratoepithelin
Cutaneous lichen amyloidosis Keratins
Corneal lactoferrin amyloidosis Lactoferrin
Pulmonary alveolar proteinosis Surfactant protein C (SP-C)
Critical illness myopathy (CIM) Hyperproteolytic state of myosin ubiquitination

References

  1. ^ Walker LC and LeVine H (2000). "The cerebral proteopathies". Neurobiol Aging 21: 559-561. PMID 10924770.
  2. ^ Friedrich O (2006). "Critical illness myopathy: what is happening?". Curr Opin Clin Nutr Metab Care 9: 403-409. PMID 16778569.
  3. ^ Walker LC, LeVine III H (2000). "The cerebral proteopathies: Neurodegenerative disorders of protein conformation and assembly". Mol Neurobiol 21: 83-95. PMID 11327151.
  4. ^ Chiti F, Dobson CM (2006). "Protein misfolding, functional amyloid, and human disease". Ann Rev Biochem 75: 333-366. PMID 16756495.
  5. ^ Carrell RW, Lomas DA (1997). "Conformational disease". Lancet 350: 134-138. PMID 9228977.
  6. ^ Dobson CM (1999). "Protein misfolding, evolution and disease". TIBS 24: 329-332. PMID 10470028.
  7. ^ Prusiner SB (2001). "Shattuck lecture—Neurodegenerative diseases and prions". N Engl J Med 344: 1516-1526. PMID 11357156.
  8. ^ Zou WQ, Gambetti P (2005). "From microbes to prions: the final proof of the prion hypothesis". Cell 121: 155-157. PMID 15851020.
  9. ^ Walker LC, LeVine H, Mattson MP, Jucker M (2006). "Inducible proteopathies". TINS 29: 438-443. PMID 16806508.
  10. ^ Meyer-Luehmann M, et al. (2006). "Exogenous induction of cerebral β-amyloidogenesis is governed by agent and host". Science 313: 1781-1784. PMID 16990547.

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