The unstable repeats--three evolving faces of neurological disease

Abstract

Disorders characterized by expansion of an unstable nucleotide repeat account for a number of inherited neurological diseases. Here, we review examples of unstable repeat disorders that nicely illustrate three of the major pathogenic mechanisms associated with these diseases: loss of function typically by disrupting transcription of the mutated gene, RNA toxic gain of function, and protein toxic gain of function. In addition to providing insight into the mechanisms underlying these devastating neurological disorders, the study of these unstable microsatellite repeat disorders has provided insight into very basic aspects of neuroscience.

Figure 1

Pathogenic mechanisms for Fragile X syndrome (FXS), Fragile X tremor-ataxia syndrome (FXTAS) and myotonic dystrophy (DM), and the polyglutamine diseases spinocerebellar ataxia type 1 (SCA1) and spinal bulbar muscular atrophy (SBMA).

Figure 2

Key elements of FXS (A) The fragile X chromosome. The fragile site indicated by arrow. (B) Alleles of FMR1. (C) Important FMRP features. Nuclear localization signal (NLS) and nuclear export signal (NES). K-homology domain (KH) and Arginine-Glycine-Glycine box (RGG) indicated. Agent domains are part of a family of Tudor domains that interact with certain methylated amino acids. The scale is amino acid number.

Figure 3

Key structural features of the androgen receptor (SBMA) and ataxin-1 (SCA1). (A) Schematic depiction of the androgen receptor protein. Features depicted are: Q)n, polymorphic polyglutamine tract; NTD, N-terminal domain; DBD, DNA binding domain; NLS, nuclear location signal; LBD, ligand binding domain; AF1, transcription activation function 1 region; AF2, transcription activation function 2 region. (B) Diagram of the Ataxin-1 protein. Features depicted are: Q)n, polymorphic polyglutamine tract; AXH, ataxin-1/HBP1 homology domain; NLS, nuclear location signal (expanded to indicate location of S776, serine 776, 14-3-3 LM, 14-3-3 binding site; ULM, binding site for RBM17 and U2AF65); SAR, self-association region; RNA binding region; CIC, binding region for Capicua.