The nuclear envelope: an intriguing focal point for neurogenetic disease

Abstract

Mutations in genes encoding nuclear envelope proteins cause a wide range of inherited diseases, many of which are neurological. We review the genetic causes and what little is known about pathogenesis of these nuclear envelopathies that primarily affect striated muscle, peripheral nerve and the central nervous system. We conclude by providing examples of experimental therapeutic approaches to these rare but important neuromuscular diseases.

Fig. 1

Schematic diagram of a typical eukaryotic cell with a portion of the nuclear envelope indicated by a rectangle. A schematic blow-up of the nuclear envelope to the right shows that it is composed the nuclear membranes, nuclear pore complexes, and nuclear lamina. The perinuclear space, a continuation of the ER lumen, separates the inner from out nuclear membranes. Proteins secreted into the ER, such as torsinA (TOR1A), can therefore reach the perinuclear space. KASH domain proteins such as large actin-binding nesprin-2 isoforms concentrate in the outer nuclear membrane by binding to inner nuclear membrane SUN proteins within the perinuclear space. The nuclear lamina is a meshwork of intermediate filaments on the inner aspect of the inner nuclear membrane and is composed of proteins called lamins. The lamina is associated with integral proteins of the inner nuclear membrane, with examples shown being MAN1, lamina-associated polypeptide-1 (LAP1), a SUN protein, lamina-associated polypeptide-2β (LAP2 2β), lamin B receptor (LBR), emerin, and a small nesprin-1 isoform. The general structure of lamins is shown (not to scale) in the lower insert. Lamins have α-helical rod domains that are conserved among all intermediate filament proteins and head and tail domains that vary in sequence among members of intermediate filament protein family. Within the tail domain, lamins contain a nuclear localization signal (NLS) that is recognized for active transport into the nucleus and an immunoglobulin-like fold (Ig fold). Most lamins have a CAAX motif at their carboxyl-termini that acts as a signal to trigger a series of chemical reactions leading to modification of the cysteine by fanesylation and carboxymethylation. Reprinted from Developmental Cell, Volume 17 / Issue 5, William T. Dauer and Howard J. Worman, The Nuclear Envelope as a Signaling Node in Development and Disease, Pages 626-638, Copyright 2009, with permission from Elsevier (reference [4]).