• (i) self proteins that can be refolded and/or disaggregated,
  
  
• (ii) self proteins that are "hopeless cases" fated to enter the proteolytic pathway,
  
  
• (iii) not-self proteins that, having aggregated, are fated to enter the peptide-presentation pathway, and
  
  
• (iv) self proteins selected from an "infinite regress repertoire" of individual-specific proteins which coaggregate with (iii).

     Diseases associated with protein aggregates (e.g. trinucleotide repeat diseases, prion diseases) may help us understand the role of protein aggregation and chaperones in these intracellular self/not-self discriminations (leading to detection and elimination of a cell with foreign nucleic acid or with a mutated oncogene; Forsdyke 1995, 1999).

    There is growing evidence that foreign (not-self) nucleic acid, by way of double-stranded RNA (dsRNA), can trigger post-transcriptional gene silencing (Fire 1999), which can be temperature-dependent (Fortier and Belote 2000). Consistent with this, self-RNAs are "purine loaded" thus preventing inadvertent formation of self-dsRNA, an adaptation which is particularly apparent in thermophiles (Lao and Forsdyke 2000). 

    dsRNA can trigger a protein kinase (PKR) and upregulate expression of various interferon and MHC protein genes. Trinucleotide repeats can form dsRNA hairpins, which also activate PKR (Tian et al. 2000). 

    If some disease features were the result of intracellular alarms triggered by dsRNA, this would explain the difficulty of correlating these features with protein aggregation. Formation of a sufficient length of dsRNA might lead to cell death either by apoptosis, or by switch of molecular chaperones from protein-disaggregation mode to protease + peptide-presentation mode, allowing cytotoxic T-cell recognition of MHC-peptide complexes (Forsdyke 1999).

    There are repeats in human and yeast prion-precursor genes, whose RNAs can adopt dsRNA structures (Poisson and Barrette 2000), but it is not known if these can activate PKR. Some prion diseases require both internal prion-precursor genes and exogenous agents (Hunter et al. 1997). These agents might induce pyrexia and/or activate PKR resulting in chaperone-mode switching for presentation of peptides from prion aggregates. 

    The mode switch might be evident as a change from one type of chaperone (e.g. constitutive hsp70) to another (e.g. inducible hsp70; Menoret et al. 1995). Intriguingly, in bacteria a single protein has the capacity to switch from chaperone mode to proteolytic mode as temperature increases (Spiess et al. 1999).

Fire A (1999) RNA-triggered gene silencing. Trends. Genet. 15, 358-363.

Forsdyke DR (1995) Entropy-driven protein self-aggregation as the basis for self/not-self discrimination in the crowded cytosol. J. Biol. Sys. 3, 273-287

Forsdyke DR (1999) Heat shock proteins as mediators of aggregation-induced 'danger' signals: implications of the slow evolutionary fine-tuning of sequences for the antigenicity of cancer cells. Cell Stress & Chaperones 4: 205-210

Fortier E and Belote JM (2000) Temperature-dependent gene silencing by an expressed inverted repeat in Drosophila. Genesis 26: 240-244.

Hunter N Cairns D Foster JD Smith G Goldmann W and Donnelly K (1997) Is scrapie solely a genetic disease. Nature 386, 137.

Lao PJ and Forsdyke DR (2000) Thermophilic bacteria strictly obey Szybalski's transcription direction rule and politely purine-load RNAs with both adenine and guanine. Genome Res. 10, 228-236

Menoret A Patry Y Burg C Le Pendu J (1995) Co-segregation of tumor immunogenicity with expression of inducible but not constitutive hsp70 in rat colon carcinomas. J. Immunol. 155: 740-747.

Poisson G and Barrette I (2000) Les maladies du prion pourraient etre un vestige d'un ancien monde de l'ARN. Unpublished communication to Congres 68 de l'Association Canadienne-Francaise pour l'Avancement des Sciences, Montreal. [Later published as Barrette I, Poisson G, Gendron P, et al. Pseudoknots in prion protein mRNAs confirmed by comparative sequence analysis and pattern searching. Nucleic Acids Res. (2001) 29, 753-758]

Spiess C, Bell A, Ehrmann M (1999) A temperature-dependent switch from chaperone to protease in a widely conserved heat shock protein. Cell 97: 339-347.

Tian B, White RJ, Xia T, Welle S, Turner DH, Mathews MB and Thornton CA (2000) Expanded CUG repeat RNAs form hairpins that activate the double-stranded RNA-dependent protein kinase PKR. RNA 6, 79-87.