Genetic mutations strengthen functional association of LAP1 with DYT1 dystonia and muscular dystrophy

Abstract

Lamina-associated polypeptide 1 (LAP1) is a ubiquitously expressed integral protein of the inner nuclear membrane. It interacts physically with lamins, torsinA, emerin and protein phosphatase 1; potentially providing a pivotal mechanism for transducing signals across the inner nuclear membrane. In neurons a functional protein complex is formed, comprising LAP1 and torsinA and in skeletal muscle LAP1 and emerin likewise form a protein complex. Several isoforms of LAP1 have been reported across species. However, in humans only two isoforms have been described, LAP1B and LAP1C. The latter has only recently been reported, but its physiological function and mode of action are not clear. The first TOR1AIP1 (gene encoding LAP1) mutation identified is a single nucleotide deletion resulting in a frameshift and a putative truncated LAP1B protein (Turkish mutation). This has deleterious effects associated with a specific form of muscular dystrophy. A second point mutation, affecting both human LAP1 isoforms, was also recently described. This mutation involves the replacement of a single glutamic acid to alanine at position 482 (Moroccan Mutation), thereby causing severe dystonia, cerebellar atrophy and cardiomyopathy.

This review focuses on the recently described human LAP1 isoform (LAP1C), the two recently reported LAP1 mutations and post-translational LAP1 modifications. The latter play an important role in regulating this protein. These scientific contributions strengthen the role of LAP1 in DYT1 dystonia and muscular dystrophy.

Introduction

Proteins of the inner nuclear membrane (INM) are receiving significant attention given the fundamental roles they play in the maintenance of the nuclear envelope (NE) architecture. The INM receives and integrates multiple signals, which must be sorted and coordinated [1]. These aspects are important for all the housekeeping cellular activities and are fundamental during cell division, a process involving nuclear disassembly and its subsequent assembly. Furthermore, it appears that the INM embedded proteins, with the capacity to bind and/or modify chromatin, may be critical in determining the characteristics of differentiated cells. Many INM proteins have been described, among them, emerin, MAN1, Nurim, Dpy19L1 to L4, SUN1 and SUN2, AKAP 149, lamin B receptor (LBR) and lamina-associated polypeptide 1 and 2 (LAP1, LAP2) [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12]. Several tumors exhibit abnormal nuclear structures which are likely to involve INM proteins [13]. These morphological alterations appear to be involved in carcinogenesis and have assisted in tumor diagnosis. Many other diseases involving the lamins and associated INM proteins have been intensively studied; these are collectively referred to as laminopathies or nuclear envelopathies [14], [15]. Emerin provided the first link between an INM protein and a human disorder. Emerin is associated with a rare human genetic disease, the X-linked form of Emery–Dreifuss muscular dystrophy [12], [16]. Other examples are the mutations of the LMNA gene (encodes lamin A and C) which are associated with over a dozen different diseases, including cardiac and muscular dystrophies, lipodystrophies and progeria (accelerated aging) [17]. The heterogenous nature of the resulting human disorders reflects the wide array of cellular functions involving lamins, namely resistance of cells to mechanical stress, contribution to structural nuclear integrity, regulation of chromatin structure and gene transcription. Many other proteins interact with lamins, among them the LAP protein family, known to bind both A- and B-type lamins. Moreover, LAP1 binds directly to lamins and indirectly to chromosomes [7]. Therefore LAP1 appears be involved in the positioning of lamins and chromatin in close proximity to the NE, thus contributing to the maintenance of the NE structure [18], [19].

LAP1 is encoded by the TOR1AIP1 gene and is a type-2 integral membrane protein, located in the INM [6], [7], [20]. LAP1 interacts with torsinA and emerin. In fact it appears that the protein complexes associated with the INM are responsible for the tissue specific laminopathies [21] and not the individual proteins.

LAP1 is a pivotal INM associated protein, capable of transducing signals across the INM [21]. It is functionally relevant across many tissues; from muscle, where it associates with emerin, to neurons where it associates with torsinA. As already mentioned LAP1 associates with both lamins and chromosomes. The interaction between LAP1 and lamins appears to be important during interphase, targeting lamins to the nuclear envelope (NE) and contributing to the maintenance of the NE architecture. During prometaphase (NE disassembly), LAP1 seems to redistribute throughout the endoplasmic reticulum (ER), and lose its association to chromosomes and lamins, thus contributing to the NE breakdown [6], [7], [19], [22]. Recently it was shown that, during the cell cycle, LAP1 plays a role in centrosome distancing from the nuclear envelope [23]. This reinforces a role for LAP1 as a key player participating in NE structural maintenance, during progression of the cell cycle. It is particularly noteworthy that LAP1 knockdown resulted in a decrease of mitotic cells and reduced levels of α-tubulin acetylated and lamin B1 [23]. LAP1 is highly phosphorylated during mitosis. In fact, it is plausible that LAP1 is regulated by protein phosphorylation during mitosis, as has been reported for other nuclear proteins [24], [25]. Even so LAP1 function is unclear, and other functions have been attributed to this protein, for example, it has been associated with torsinA ATPase regulation.