Nesprin-1/2: roles in nuclear envelope organisation, myogenesis and muscle disease

Abstract

Nesprins (nuclear envelope spectrin repeat proteins) are multi-isomeric scaffolding proteins. Nesprin-1 and -2 are highly expressed in skeletal and cardiac muscles and together with SUN (Sad1p/UNC84) domain-containing proteins form the LInker of Nucleoskeleton and Cytoskeleton (LINC) complex at the nuclear envelope in association with lamin A/C and emerin. Mutations in nesprin-1/2 have been found in patients with autosomal dominant Emery-Dreifuss muscular dystrophy (EDMD) as well as dilated cardiomyopathy (DCM). Several lines of evidence indicate that compromised LINC complex function is the critical step leading to muscle disease. Here, we review recent advances in our understanding of the functions of nesprin-1/2 in the LINC complex and mechanistic insights into how mutations in nesprin-1/2 lead to nesprin-related muscle diseases, in particular DCM and EDMD.

Regulation of Neuronal Survival and Axon Growth by a Perinuclear cAMP Compartment

“…We now show that nesprin-1 is present on the nuclear envelope in hippocampal neurons (Fig. 1B), just as we have previously shown for mAKAP␣ (Michel et al, 2005) and as found for nesprin-1 in other neurons and other cell types (Gros-Louis et al, 2007;Zhou et al, 2018). Expression of a GFP-tagged fragment encoding the mAKAP spectrin-repeat domains (amino acid residues 586 -1286, "mAKAP-SR-GFP"; Fig.…”

“…For live cell imaging, Cos-7 cells were plated onto 25-mm-diameter sterilized glass coverslips in 6-well plates and were either transfected with polyethylenimine or infected with adenovirus at 60 -70% confluence and allowed to grow for 24 -48 h before live cell imaging. Nesprin-1␣ fusion proteins are not properly localized to the nuclear envelope when grossly overexpressed due to saturation of Klarsicht/ANC-1/Syne-1 homology (KASH)-SUN domain protein-protein interactions (Zhou et al, 2018). Only Cos-7 cells and neurons with epifluorescence for PN-AKAR and the other nesprin-1␣ fusion proteins restricted to the nuclear envelope were included in the studies.…”

“…Initial characterization of PN-AKAR4 was performed in Cos-7 cells, a heterologous cell line that lacks nesprin-1␣ and mAKAP. When the fusion biosensor was expressed at moderate levels to avoid saturation of the KASH domain-mediated nuclear envelope localization mechanism (Zhou et al, 2018), cerulean and cpVE172-E172 fluorescence were limited to the nuclear envelope (Fig. 2B).…”

Syncrip/hnRNPQ is required for activity-induced Msp300/Nesprin-1 expression and new synapse formation

“…and SYNE-1/2 both encode Nesprin proteins that perform many similar functions, including regulation of glutamate receptor expression (Cottrell et al, 2004;Morel et al, 2014) and positioning of myonuclei (Stroud et al, 2017;Volk, 2013;Wang et al, 2015;Zhou et al, 2018a). The functional role of Nesprins in the nervous system is more enigmatic and requires further attention because mutations in SYNE-1 and -2 are strongly linked to recessive forms of hereditary cerebellar and extra-cerebellar ataxias in humans Gros-Louis et al, 2007;Noreau et al, 2013;Synofzik et al, 2016;Wiethoff et al, 2016).…”

“…The Nesprins are encoded by synaptic nuclear envelope-1 and -2 (SYNE-1 and -2), which contain at least 80 disease-related variants that cause cerebellar ataxias or muscular dystrophies (Zhou et al, 2018b). The molecular function of Nesprins and their role in muscular diseases are relatively well studied in mouse models of SYNE-1 and SYNE-2 (Zhou et al, 2018a) in relation to nucleo-cytoplasmic and cytoskeletal organization and function, but the function of Nesprins in neurological disorders…”