Proteinopathy
| Proteinopathy | |
|---|---|
 | |
| Micrograph of a section of the cerebral cortex from a person with Alzheimer's disease, immunostained with an antibody to amyloid beta (brown), a protein fragment that accumulates in amyloid plaques and cerebral amyloid angiopathy. 10X microscope objective. |
In
mad cow disease) and other prion diseases, Alzheimer's disease, Parkinson's disease, amyloidosis, multiple system atrophy, and a wide range of other disorders.[2][4][5][6][7][8] The term proteopathy was first proposed in 2000 by Lary Walker and Harry LeVine.[1]
The concept of proteopathy can trace its origins to the mid-19th century, when, in 1854,
oligomers are toxic to the cells of an affected organ, and that amyloidogenic proteins in their fibrillar form may be relatively benign.[11][12]
Pathophysiology
In most, if not all proteinopathies, a change in the
synucleinopathy
. 40X microscope objective.The likelihood that proteinopathy will develop is increased by certain
Lewy bodies) in the brain.[26]
It is hypothesized that chaperones and co-chaperones (proteins that assist protein folding) may antagonize proteotoxicity during aging and in protein misfolding-diseases to maintain proteostasis.[27][28][29]
Seeded induction
Some proteins can be induced to form abnormal assemblies by exposure to the same (or similar) protein that has folded into a disease-causing conformation, a process called 'seeding' or 'permissive templating'.TDP-43).[45]
In all of these instances, an aberrant form of the protein itself appears to be the pathogenic agent. In some cases, the deposition of one type of protein can be experimentally induced by aggregated assemblies of other proteins that are rich in β-sheet structure, possibly because of structural complementarity of the protein molecules. For example, AA amyloidosis can be stimulated in mice by such diverse
curli fibrils from the bacterium Escherichia coli.[46] AII amyloid can be induced in mice by a variety of β-sheet rich amyloid fibrils,[47] and cerebral tauopathy can be induced by brain extracts that are rich in aggregated Aβ.[48] There is also experimental evidence for cross-seeding between prion protein and Aβ.[49]
In general, such heterologous seeding is less efficient than is seeding by a corrupted form of the same protein.
List of proteinopathies
| Proteinopathy | Major aggregating protein |
| Alzheimer's disease[16] | Amyloid β peptide ( tauopathies )
|
| Cerebral β- amyloid angiopathy[50]
|
Amyloid β peptide ( Aβ )
|
| Retinal ganglion cell degeneration in glaucoma[51] | Amyloid β peptide ( Aβ )
|
Prion diseases (multiple)[52]
|
Prion protein
|
synucleinopathies (multiple)[53]
|
α-Synuclein |
Tauopathies (multiple)[54]
|
Microtubule-associated protein tau (Tau protein) |
FTLD) (Ubi+, Tau-)[55]
|
TDP-43
|
FUS[55]
|
Fused in sarcoma (FUS) protein |
C9ORF72, ubiquilin-2 (UBQLN2 )
| |
| Proteins with tandem glutamine expansions | |
| Familial British dementia[50] | ABri |
| Familial Danish dementia[50] | ADan |
| Hereditary cerebral hemorrhage with amyloidosis (Icelandic) (HCHWA-I)[50]
|
Cystatin C |
| CADASIL[60] | Notch 3
|
| Alexander disease[61] | Glial fibrillary acidic protein (GFAP) |
Pelizaeus-Merzbacher disease
|
proteolipid protein (PLP)
|
| Seipinopathies[62] | Seipin |
| Familial amyloidotic neuropathy, Senile systemic amyloidosis
|
Transthyretin[63] |
| Serpinopathies (multiple)[64] | Serpins
|
| AL (light chain) amyloidosis (primary systemic amyloidosis) | Monoclonal immunoglobulin light chains[63]
|
| AH (heavy chain) amyloidosis | Immunoglobulin heavy chains[63]
|
| AA (secondary) amyloidosis | Amyloid A protein[63] |
Type II diabetes[65]
|
Islet amyloid polypeptide (IAPP; amylin )
|
| Aortic medial amyloidosis | Medin ( lactadherin)[63]
|
ApoAI amyloidosis
|
Apolipoprotein AI[63] |
| ApoAII amyloidosis | Apolipoprotein AII[63] |
| ApoAIV amyloidosis | Apolipoprotein AIV[63] |
| Familial amyloidosis of the Finnish type (FAF) | Gelsolin[63] |
| Lysozyme amyloidosis | Lysozyme[63] |
| Fibrinogen amyloidosis | Fibrinogen[63] |
| Dialysis amyloidosis | Beta-2 microglobulin[63] |
| Inclusion body myositis/myopathy[66] | Amyloid β peptide ( Aβ )
|
Cataracts[67]
|
Crystallins
|
| Retinitis pigmentosa with rhodopsin mutations[68] | rhodopsin |
| Medullary thyroid carcinoma | Calcitonin[63] |
| Cardiac atrial amyloidosis | Atrial natriuretic factor[63]
|
Pituitary prolactinoma
|
Prolactin[63] |
| Hereditary lattice corneal dystrophy | Keratoepithelin[63] |
| Cutaneous lichen amyloidosis[69] | Keratins
|
Mallory bodies[70]
|
Keratin intermediate filament proteins |
| Corneal lactoferrin amyloidosis | Lactoferrin[63] |
| Pulmonary alveolar proteinosis | Surfactant protein C (SP-C)[63] |
| Odontogenic (Pindborg) tumor amyloid | Odontogenic ameloblast-associated protein[63] |
Seminal vesicle amyloid
|
Semenogelin I[63] |
| Apolipoprotein C2 amyloidosis | Apolipoprotein C2 (ApoC2)[63]
|
| Apolipoprotein C3 amyloidosis | Apolipoprotein C3 (ApoC3)[63]
|
Lect2 amyloidosis
|
Leukocyte chemotactic factor-2 (Lect2)[63] |
| Insulin amyloidosis | Insulin[63] |
| Galectin-7 amyloidosis (primary localized cutaneous amyloidosis) | Galectin-7 (Gal7)[63] |
| Corneodesmosin amyloidosis | Corneodesmosin[63] |
| Enfuvirtide amyloidosis[71] | Enfuvirtide[63] |
| Cystic fibrosis[72] | cystic fibrosis transmembrane conductance regulator (CFTR) protein |
| Sickle cell disease[73] | Hemoglobin |
| Plasma cell dyscrasias (monoclonal gammopathies) | gamma globulin |
Exfoliation syndrome[74] aka pseudoexfoliation syndrome
|
aggregated fibrillar material esp. LOXL1 |
Management
The development of effective treatments for many proteopathies has been challenging.antibodies to neutralize specific proteins by active or passive immunization.[79] In some proteopathies, inhibiting the toxic effects of protein oligomers might be beneficial.[80]
For example, Amyloid A (AA) amyloidosis can be reduced by treating the
molecules bound together). Stabilization prevents individual TTR molecules from escaping, misfolding, and aggregating into amyloid.[84][85]
Several other treatment strategies for proteopathies are being investigated, including
immune cells.[84][81][86][87] In some cases, multiple therapeutic agents may be combined to improve effectiveness.[81][88]
Additional images
-
Micrograph of tauopathy (brown) in a neuronal cell body (arrow) and process (arrowhead) in the cerebral cortex of a patient with Alzheimer's disease. Bar = 25 microns (0.025mm).
See also
- Amyloidosis
- Neurofibrillary tangles
- Protein toxicity
- Prion
- Transmissible spongiform encephalopathy
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