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Review
. 2022 Jan 25;23(3):1329.
doi: 10.3390/ijms23031329.

Emerging Connections between Nuclear Pore Complex Homeostasis and ALS

Sunandini Chandra  1 , C Patrick Lusk  1
Affiliations
Review

Emerging Connections between Nuclear Pore Complex Homeostasis and ALS

Sunandini Chandra et al. Int J Mol Sci. .

Abstract

Developing effective treatments for neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) requires understanding of the underlying pathomechanisms that contribute to the motor neuron loss that defines the disease. As it causes the largest fraction of familial ALS cases, considerable effort has focused on hexanucleotide repeat expansions in the C9ORF72 gene, which encode toxic repeat RNA and dipeptide repeat (DPR) proteins. Both the repeat RNA and DPRs interact with and perturb multiple elements of the nuclear transport machinery, including shuttling nuclear transport receptors, the Ran GTPase and the nucleoporin proteins (nups) that build the nuclear pore complex (NPC). Here, we consider recent work that describes changes to the molecular composition of the NPC in C9ORF72 model and patient neurons in the context of quality control mechanisms that function at the nuclear envelope (NE). For example, changes to NPC structure may be caused by the dysregulation of a conserved NE surveillance pathway mediated by the endosomal sorting complexes required for the transport protein, CHMP7. Thus, these studies are introducing NE and NPC quality control pathways as key elements in a pathological cascade that leads to C9ORF72 ALS, opening entirely new experimental avenues and possibilities for targeted therapeutic intervention.

Keywords: C9ORF72 ALS; CHMP7; ESCRT; NPC injury; POM121; nuclear quality control; nuclear transport.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic of NPC embedded in the nuclear envelope. Major architectural assemblies and relative position of individual nups are indicated. Nups, in red, are depleted in C9-ALS. ONM is outer nuclear membrane; INM is inner nuclear membrane.
Figure 2
Figure 2
Model of the NPC injury cascade observed in C9-ALS IPSNs with key unknown questions (Q). NPC injury is thought to proceed in a stepwise process (left to right) beginning with an insult that leads to CHMP7 nuclear import or inhibition of its nuclear export by XPO1 (Q1). This aberrant accumulation of CHMP7 leads to the loss of the linchpin POM121 through a mechanism that remains ill defined (Q2), which in turn results in the loss of additional nups (Q3). The overall nup loss burden (depicted as graying of the NPC) is suggested to impact nuclear transport and disrupt Ran and TDP-43 localization.
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