Untethering the nuclear envelope and cytoskeleton: biologically distinct dystonias arising from a common cellular dysfunction

Abstract

Most cases of early onset DYT1 dystonia in humans are caused by a GAG deletion in the TOR1A gene leading to loss of a glutamic acid (ΔE) in the torsinA protein, which underlies a movement disorder associated with neuronal dysfunction without apparent neurodegeneration. Mutation/deletion of the gene (Dst) encoding dystonin in mice results in a dystonic movement disorder termed dystonia musculorum, which resembles aspects of dystonia in humans. While torsinA and dystonin proteins do not share modular domain architecture, they participate in a similar function by modulating a structural link between the nuclear envelope and the cytoskeleton in neuronal cells. We suggest that through a shared interaction with the nuclear envelope protein nesprin-3α, torsinA and the neuronal dystonin-a2 isoform comprise a bridge complex between the outer nuclear membrane and the cytoskeleton, which is critical for some aspects of neuronal development and function. Elucidation of the overlapping roles of torsinA and dystonin-a2 in nuclear/endoplasmic reticulum dynamics should provide insights into the cellular mechanisms underlying the dystonic phenotype.

Figure 1

Schematic diagram of the AAA⁺ torsin protein family. The key features of torsinA, torsinB, torsin2, and torsin3 are shown, including the signal sequence (SS; turquoise), hydrophobic domain (Hypb; grey), and AAA⁺ domain (purple). The AAA⁺ domain of torsinA, illustrated in more detail, consists of Walker A/B (green) motifs, sensor I/II (orange) motifs, and six conserved cysteines (C). Also, the total number of amino acids (a.a.) for each protein and the overall percentage similarity with torsinA are indicated. In torsin2, the Hydb domain is absent and torsin3 has a longer Hydb domain. The 10 a.a. region in torsinA in which the glutamic acid deletion underlying DYT1 dystonia occurs is shown in detail. Conserved a.a. residues in this region in other members of the torsin family are underlined (figure revised from Jungwirth et al. [26] and Zhu et al. [54]).

Figure 2

Structural representation of dystonin protein isoforms. (a) Illustration of the modular domain structure of tissue specific dystonin isoforms. Three tissue-specific isoforms have been identified; muscle (dystonin-b), neuronal (dystonin-a), and epithelial (dystonin-e). (b) Dystonin-a and b isoforms vary at the N-terminus, resulting in three distinct isoforms. The isoform 1 variant possesses a sequence coding for an ABD at the N-terminus. The isoform 2 variant contains sequence coding for a highly conserved N-terminal TM domain, while the isoform 3 variant contains sequence coding for a conserved MYR motif.

Figure 3

Hypothesized model for torsinA, dystonin-a2, and their common associated partner, nesprin-3α. This schematic represents the associations between torsinA and dystonin-a2 with nesprin-3α, a type II TM protein in the ONM that contains a C-terminal KASH domain within the lumenal space of the NE. Nesprin-3α interacts with SUN proteins (green and gray), which span the INM of the NE, through its KASH domain (purple). TorsinA (red hexameric circles) associates with nesprin-3α and regulates its interaction with SUN proteins. The N-terminus of nesprin-3α binds to the plakin family member, plectin, which in turn links to IFs through its IF-binding domain (IFBD; blue). Dystonin-a2 has a TM domain (dark blue) at the N-terminus, which embeds in the ONM of the NE and associates with nesprin-3α. Like plectin, dystonin-a isoforms are members of the plakin protein family and are characterized by SR domains indicated by the “chain shape” (gray) and an ABD (pink) in the N-terminal region. The dystonin-a2 isoform also possesses a C-terminal MTBD through which it associates with microtubules. Collectively, these proteins function to bridge the NE and ER with the three major cytoskeleton networks present in eukaryotes.