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protein misfolding diseases

Saturday 14 January 2006

Definition: Misfolding diseases are a wide group of devastating disorders characterized by the accumulation of pathological protein aggregates.

Although these disorders still lack an effective treatment, new antibody-based strategies are emerging and entering clinical trials. The intrabody approach is a gene-based technology developed to neutralize or modify the function of intracellular and extracellular target antigens.

Because intrabodies can potentially target all the different isoforms of a misfolding-prone protein, including pathological conformations, they are emerging as therapeutic molecules for the treatment of misfolding diseases, including Alzheimer’s, Parkinson’s, Huntington’s and prion diseases.

Most proteins in the cell adopt a compact, globular fold that determines their stability and function. Partial protein unfolding under conditions of cellular stress results in the exposure of hydrophobic regions normally buried in the interior of the native structure.

Interactions involving the exposed hydrophobic surfaces of misfolded protein conformers lead to the formation of toxic aggregates (protein aggregation), including oligomers, protofibrils and amyloid fibrils.

A significant number of human diseases (e.g. Alzheimer disease, Parkinson disease, Huntington disease, amyotrophic lateral sclerosis and type II diabetes) are characterised by protein misfolding and protein aggregation.

Folding in the endoplasmic reticulum (ER) must couple protein-synthesis pathways operating outside of the compartment with ER-assisted folding (ERAF) pathways in the lumen.

Chaperone-mediated folding imbalances that are associated with numerous misfolding diseases, including diabetes, trigger the unfolded-protein response (UPR), using both transcriptional and translational pathways to correct the problem.

Protein Folding Associated Diseases

Disease OMIM Main aggregate component
Neurodegenerative diseases - -
amyotrophic lateral sclerosis 1 (ALS1) MIM.105400 Superoxide dismutase 1 (SOD1) (wt or mutant) + Unknown Proteins
Alzheimer disease * AB peptides (plaques) (APP); tau protein (MAPT) (neurofibrillary tangles NFTs)
spongiform encephalopathies * Prion protein PrP
Parkinson disease * alpha-synuclein (SNCA) (wt or mutant)
frontotemporal dementias (FTDs) * Tau (wt or mutant) (MAPT)
familial amyloid polyneuropathy I * transthyretin (over 45 mutants) (TTR)
familial amyloid polyneuropathy III MIM.107680 Apolipoprotein AI (fragments) (APOA1)
polyglutamine repeat diseases with neurodegeneration - -
Huntington disease MIM.143100 huntingtin (HTT)
X-linked spinal and bulbar muscular atrophy 1 (SMAX1) MIM.313200 Androgen receptor (AR) [whole or poly(Q) fragments]
spinocerebellar ataxias (SCAs) * Ataxins [whole or poly(Q) fragments]
spinocerebellar ataxia 17 MIM.607136 TATA box-binding protein (TBP) [whole or poly(Q) fragments]
amyloidoses - -
atrial amyloidosis - atrial natriuretic factor (ANF)
hereditary amyloidosis type 5 (finnish type) MIM.105120 gelsolin (GSN) (71 amino acid fragment)
familial visceral amyloidosis (amyloidosis type 8) - lysozyme (LYZ) (whole or fragments)
hemodialysis-related amyloidosis - B2-microglobulin
hereditary renal amyloidosis - Fibrinogen A alpha chain (FGA), transthyretin (TTR), apolipoproteins A1 (APOA1)and A2 (APOA2), lysozyme (LYZ), gelsolin (GSN), cystatin C (CST3)
hereditary cerebral amyloid angiopathy - cystatin C (CST3) (minus a 10-residue fragment)
injection-localised amyloidosis - insulin (ISN)
medullary carcinoma of the thyroid - calcitonin (CALCA) (fragment)
primary systemic amyloidosis - Ig light chains (IGL and IGK) (whole or fragments)
secondary systemic amyloidosis - serum amyloid A (SAA) (whole or 76-residue fragment)
senile systemic amyloidosis - transthyretin (TTR) (whole or fragments)
type 2 diabetes - amylin (fragment)


Over the past five years, outstanding progress has been made in the development of therapeutic strategies targeting these diseases. Three promising approaches include: (1) inhibiting protein aggregation with peptides or small molecules identified via structure-based drug design or high-throughput screening; (2) interfering with post-translational modifications that stimulate protein misfolding and aggregation; and (3) upregulating molecular chaperones or aggregate-clearance mechanisms.

Small-molecule inhibitors could be useful to help rebalance protein synthesis with ERAF pathways through the ribosomal initiating factor eIF2alpha.

Reprogramming stress pathways with drugs provides a potential new approach for balancing ER-protein load with cellular-folding capacity, thus correcting disease.

See also

- protein folding


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