Prion Repeats and tri-nucleotide repeat neurological diseases

Adapted from McLaughlin, B et al Am.J.Human Genetics 59:561-569 1996

Quite a few neurological disorders [see table below] are turning out to have a bizarre genetic basis consisting of variations in a short region that is repeated a few to hundreds of times. If in a coding open reading frame (ORF), the repeat is translated; if in a leader or trailer sequence (untranslated reading frame, UTR) it is not. The disease condition is associated with increasingly long repeats. Disease onset can be earlier in subsequent generations if the repeat length has increased.

Recall that prion protein contains a repeat region, typically a highly conserved octapeptide repeated 5-6 times [e.g., PQGGGGWGQ PHGGGWGQ PHGGGWGQ PHGGGWGQ PHGGGWGQ PHGGGGWGQ]. Furthermore, there are numerous instances where increased length (from 1 to 9 additional repeats) leads to familial CJD. The function of this domain in prion protein is not understood, but it is worth exploring whether it has anything in common with (tri-nucleotide and longer) repeat neurological conditions.

McLaughlin et al describe the situation in Huntington Disease, a condition associated with a simple CAG tri-nucleotide repeat (giving poly-glutamine) that is innocuous at the level of 11-34 repeats but becomes a serious neurological disorder when 37-180 repeats in length. Three models are considered by way of explanation:

  1. An RNA binding protein interacts with the repeat and alters the amount of Huntington protein produced.
  2. An RNA chaparone protein affects the subcellular distribution of the Huntington mRNA ( causing polarized translation to take place, i.e., locally at a dendritic synapse).
  3. An RNA binding protein is titrated away by all the extra repeats [sink theory] from other important mRNAs, causing a subtle imbalance of their production that leads to the disease state.
These models have some attractiveness for the spongiform encephalopathies. Like many of the 14-15 known conditions, it is a neurological disorder. Prion protein has a repeat region to which it is difficult to assign a function at the protein level, suggesting a role for regulation of transcription or translation, that is, the repeats are mostly significant at the nucleotide level. A disease condition is known to result when the length of the repeat increases. Genetic changes in the octapeptide region have always been insertions or deletions of one or more repeat units, never just a single amino acid. It is hard to see how inserting 72 additional amino acids could still allow a functioning product if it were in a domain integral to prion end function or how such a massive alteration could parallel subtle conformational effects of point mutations. Prion protein can be strongly localized at synapses [Neuroscience Letters v159 p111 1994] so could benefit from chaperoning for the purpose of local synthesis). The sink model is not unlike theories proposed for a perturbed equilibrium of prion and heat shock protein 60.


ConditionAcronymDNA RepeatpositionAAnormal repeatsdisease repeats
Huntington Disease HD CAG ORF gln 11-34 37-180
Spinal-bulbar muscular atrophy SBMA CAG ORF gln . 37-180
Spinoocerebellar ataxia 1 SCA1 CAG ORF gln . 37-180
Dentatorubral-pallidoluysian atrophy DRPLA CAG ORF gln . 37-180
Machado- Joseph disease MJD CAG ORF gln . 37-180
.. . . . . .
Myotonic dystrophy MD CTG UTR --- . 200-2000
Fragile X syndrome FRAXA CGG UTR --- . 200-2000
Fragile X syndrome FRAXE CGG UTR --- . 200-2000
.. . . . . .
D4 dopamine receptor D4DR . . . 2-11 7
(Other mRNAs which contain poly-CAG tracts include androgen receptor, TATA-binding protein, achaete scute homologue, pim-i proto oncogene, natruretic peptide, preproenkepahlin (8), and calmodulin-1.)