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.
Highlights
Introduction to Amyotrophic Lateral SclerosisBackground of Genotypic and Pathological FeaturesNeurodegenerative diseases constitute a spectrum of pathologies that includes amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Parkinson’s disease, Alzheimer’s disease and Huntington’s disease, which affect millions of people worldwide [1]
For further insight into what these pathways might be, we turn to work in non-neuronal model systems, which is revealing that there may be nuclear envelope (NE)-specific factors that contribute to the ER-associated degradation (ERAD) and autophagy of NE components such as nuclear pore complex (NPC) and integral inner nuclear membrane (INM) proteins
Defects in the nuclear transport machinery including the loss of nups within the NPC itself are central to both C9-ALS, and likely some sALS, pathogenesis
Summary
Neurodegenerative diseases constitute a spectrum of pathologies that includes amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Parkinson’s disease, Alzheimer’s disease and Huntington’s disease, which affect millions of people worldwide [1]. There remains a critical need to understand the underlying pathomechanisms at the molecular level in order to inform new therapeutic strategies Efforts to define such mechanisms benefit from genetic studies that, beginning with SOD1 28 years ago, have identified several causative genetic variants in a multitude of genes, including C9ORF72, TARDBP, FUS, ANG, MATR3, OPTN, TBK1, NEK1, C21ORF2, CHCHD10, DCTN1, TUBA4A, PFN1, SQSTM1, VCP and UBQLN2 [4,5]. These pathways could provide a roadmap forward to identifying the underlying causes of these diseases. FFiigguurree22..MMooddeelloofftthheeNNPPCC iinnjjuurryy ccaassccaaddee oobbsseerrvveedd iinn CC99--AALLSSIIPPSSNNsswwitithhkkeeyyuunnkknnoowwnnqquuesetsitoinons s ((QQ))..NNPPCCiinnjjuurryy iiss tthhoouugghhtt ttoo pprroocceeeedd iinn aa sstteeppwwiisseepprroocceessss((lleeffttttoorrigighht)t)bbeeggininnnininggwwitihthananininsusultlt tthhaattlleeaaddssttooCCHHMMPP77 nnuucclleeaarr iimmppoorrtt oorr iinnhhiibbiittiioonnooffiittssnnuucclleeaarreexxppoorrttbbyyXXPPOO11(Q(Q1)1.).TThhisisababererrarnatnt amaccaccuiunmms uiullllaadttieioofninnoeodff CC(QHH2MM),PPw77hleilcaehdadsinstottuothrtnehlreoeslssousolstfstohifnetthlhineecllhionpscisnhopPfiOnadMPdO1i2tMi1ont1h2ar1lonutuhgprhosau(gQmh3e)ca.hTmahneeiscomhvaetnhriaastlmlrnetmuhpaatilnorssesbiullrddeefinn(edde(pQic2t)e, dwahsicghrianytiunrgnorfetshueltsNiPnCth)eislossusgogfeasdteddititooniaml pnuacptsn(Quc3l)e.aTrhteraonvseproalrltnaunpdldosissrbuuprtdRenan a(nddepTicDtePd-4a3slogcraalyizinagtioonf.the NPC) is suggested to impact nuclear transport and disrupt Ran and TDP-43 localization
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