ReviewNucleocytoplasmic transport defects in neurodegeneration — Cause or consequence?
Introduction
Neurodegeneration, the progressive dysfunction and eventual loss of specific nerve cells, is characterized by distinct cytosolic or nuclear protein deposits that are considered to be pathological hallmarks of the respective neurodegenerative disorder (Fig. 1). For example in most ALS (amyotrophic lateral sclerosis) and FTD (frontotemporal dementia) patients, the RNA binding proteins (RBPs) TDP43 or, more rarely, FUS are depleted from the nucleus and aggregate in the cytoplasm of neurons and glia cells in the affected brain regions [1]. ALS and FTD are part of a continuous disease spectrum and are linked by similar molecular dysfunctions [2,3]. For instance, they can be caused by the same genetic defects, e.g. a hexanucleotide (G4C2) repeat expansion in the first intron of the C9ORF72 gene (C9-ALS/FTD) [4,5]. While this repeat expansion also results in reduced expression of the C9ORF72 protein, disease-related pathology has largely been attributed to either RNA foci formed by sense and antisense repeat RNA (C9-RNA) or to inclusions formed by dipeptide repeat proteins (DPRs), namely polyGA, -GP, -GR, -PA and -PR, generated by ATG-independent translation from both sense and antisense C9-RNA [6].
A subset of FTD patients do not display RBP aggregates, but presents with intracellular aggregates of the microtubule-binding protein Tau in so-called neurofibrillary tangles [7]. Tau tangles, together with extracellular Aβ plaques, are also a neuropathological hallmark of Alzheimer’s disease (AD) [8]. Finally, CAG nucleotide repeat expansions result in expanded polyglutamine (polyQ) stretches in proteins such as Huntingtin (HTT), ataxins or the androgen receptor (AR) and subsequent intracellular aggregation of these proteins, and are associated with Huntington disease (HD), spinocerebellar ataxias (SCA) and spinobulbar muscular atrophy (SBMA), respectively [9]. How protein aggregates in various neurodegenerative disorders arise, and how they contribute to the pathogenic process of neurodegeneration, is currently not well understood.
In recent years, nucleocytoplasmic transport has gained increasing attention in neurodegeneration research, due to some prominent links between disease-associated protein aggregates and components of the nucleocytoplasmic transport machinery: First ALS-causing mutations in the nuclear localization signal (NLS) of FUS were identified, resulting in cytoplasmic mislocalization and accumulation of FUS in stress granules (SGs) [[10], [11], [12]]. This has led to the hypothesis that impaired nuclear import of disease-linked proteins may be a key ALS pathomechanism [13]. This hypothesis was further supported by several independent genetic screens for modulators of cellular toxicity, as well as proteomic studies that identified many components of the nucleocytoplasmic transport machinery to be associated with C9-ALS/FTD [[14], [15], [16], [17], [18]]. Recently, observations of nucleocytoplasmic transport defects in AD and HD [[19], [20], [21]] with some resemblance to physiological ageing [[22], [23], [24]] have further stimulated the discussion whether disturbances in nucleocytoplasmic transport may play a more global role in neurodegenerative processes than previously anticipated.
In this review, we summarize the status quo of research on nucleocytoplasmic transport in neurodegenerative diseases, in particular ALS/FTD, AD and HD. We will discuss whether nucleocytoplasmic transport defects are actually upstream of pathological protein deposits, contributing to their formation, or rather downstream, caused by the presence of pathological protein aggregates. Furthermore, we will highlight similarities between specific features of neurodegenerative disorders and physiological ageing, and discuss recent data obtained in progeria research that might provide interesting mechanistic insights into nucleocytoplasmic transport defects in neurodegenerative diseases. Overall, we hope to point out potential gaps in our current understanding of how nucleocytoplasmic transport defects are linked to neurodegeneration, which will require more detailed analysis in the future.
Section snippets
Evidence for impaired nucleocytoplasmic transport in neurodegenerative disorders
A number of nuclear proteins, such as RBPs or transcription factors, have been reported to mislocalize and aggregate in the cytoplasm of post mortem brain or spinal cord in diverse neurodegenerative disorders (Fig. 1; [4,5,7,9,11,12,14,20,[25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45], [46], [47], [48]]). However, often it is unclear whether this is directly linked to impaired nucleocytoplasmic transport, as such
The role of the nuclear pore complex in neurodegeneration
As the NPC mediates controlled, bidirectional transport of proteins, RNA and complexes thereof between nucleus and cytoplasm, it is an obvious point of interest in search of mechanisms underlying nucleocytoplasmic transport defects in neurodegeneration.
NPCs are large multiprotein complexes (∼120 MDa in humans) composed of ∼30 individual proteins in multiple copies, so called nucleoporins (Nups) [[55], [56], [57], [58]]. The overall NPC architecture with its symmetrical core and asymmetrically
The role of NTRs in neurodegeneration
Nuclear transport receptors (NTRs), also called karyopherins, can be classified as importins or exportins, depending on the direction of cargo transport, even though some NTRs can function bidirectionally [56,128]. With ∼20 members, the Impβ superfamily is the largest class of NTRs and its members mediate import and export of both proteins and specific kinds of RNAs. NTRs of the Impβ-superfamily are ubiquitiously expressed, however their expression levels vary during development and between
Changes to the Ran system - misregulated regulators?
The differential concentration of RanGTP/GDP between nucleus and cytoplasm, generally referred to as RanGTP gradient, conveys directionality to nucleocytoplasmic transport and is maintained by spatial separation of its upstream regulators. In the nucleus, exchange of GDP to GTP is catalyzed by the chromatin-associated RanGEF, RCC1 [163]. On the cytoplasmic side, GTP hydrolysis is promoted by the RanGTPase activating protein, RanGAP, together with its accessory proteins RanBP1 or Nup358/RanBP2 [
Perspectives and open questions
Many lines of evidence indicate that nucleocytoplasmic transport is affected in several neurodegenerative diseases, however differences in the underlying mechanisms and molecular details seem to exist between distinct disorders. In order to dissect the individual pathogenic mechanisms and develop therapeutic tools, it will be essential to carefully examine the causal and temporal relationship of changes to the nucleocytoplasmic transport machinery in detail. In particular, it needs to be
Acknowledgements
We thank Lara Gruijs da Silva for helpful discussions and Dr. Ralph Kehlenbach for critical reading of the manuscript. This work was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation; Emmy Noether grant DO 1804/1-1; DO1804/3-1) and under Germany’s Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy – ID 390857198). We also acknowledge support from the Fritz Thyssen Foundation.
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