Molecular mechanisms of TRS instability.

To date several neurodegenerative disorders including myotonic dystrophy, Huntington's disease, Kennedy's disease, fragile X syndrome, spinocerebellar ataxias or Friedreich's ataxia have been linked to the expanding trinucleotide sequences. Although phenotypic features vary among these debilitating diseases, the structural abnormalities of the triplet repeat containing DNA sequences is the primary cause for all of these disorders. Expansions of the CAG repeat within coding regions of miscellaneous genes result in the synthesis of aberrant proteins containing enormously long polyglutamine stretches. Such proteins acquire toxic functions and/or may direct cells into the apoptotic cycle. On the other hand, massive expansions of various triplet repeats (i.e., CTG/CAG, CGG/CCG/, GAA/TTC) inside the noncoding regions lead to the silencing of transcription and therefore affect expression of the adjacent genes. The repetitive character of TRS allows stretches of such tracts to form slipped-stranded structures, self-complementary hairpins, triplexes or more complex configurations called "sticky DNA", which are not equally processed by some cellular mechanisms, as compared to random DNA. It is likely that the instability of the short TRS (below the threshold level) occurs due to the SILC pathway, which is driven by the DNA slippage. Accumulation of the short expansions leads to the disease premutation state where the MLC pathway becomes predominant. Independent of which mechanism is involved in the MLC pathway (replication, transcription, repair or recombination) the process of complementary strand synthesis is crucial for the TRS instability. Generally, dependent on the location of the tract which has higher potential to form secondary DNA structure, further processing of such tract may result in expansions (secondary structure formed at the newly synthesized strand) or deletions (structure present on the template strand). Analyses of molecular mechanisms of the TRS genetic instability using bacteria, yeast, cell lines and transgenic animals as models allowed the scientists to better understand the role of some major cellular processes in the development of neurodegenerative disorders in humans. However, it is necessary to remember that most of these investigations were focused on the involvement of each particular process separately. Much less of this work though was dedicated to the search for the interactions between such cellular systems that in effect could result in different rate of TRS expansions. Thus, more intensive studies are necessary in order to fully understand the phenomenon ofthe dynamic mutations leading to the human hereditary neurodegenerative diseases.