Nuclear trafficking in amyotrophic lateral sclerosis and frontotemporal lobar degeneration

Mihevc, Sonja Prpar; Darovic, Simona; Kovanda, Anja; Česnik, Ana Bajc; Župunski, Vera; Rogelj, Boris

doi:10.1093/brain/aww197

Cited by 53 publications

(36 citation statements)

References 121 publications

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“…A convergence of recent evidence has implicated errors in nucleo/cytoplasmic transport as a component of normal aging [11] as well as several neurodegenerative disorders [13], including ALS/FTD [8, 49], Huntington’s disease (Cleveland and Lagier-Tourenne, personal communication) [35, 43, 68], and other repeat expansion models [38, 51]. Studies in yeast [27] and flies [61] have identified components of nuclear transport as modifiers of toxicity in models expressing mutant TDP-43, or the C9orf72 hexanucleotide repeat expansion [17, 71].…”

Section: Discussionmentioning

confidence: 99%

Mutant TDP-43 within motor neurons drives disease onset but not progression in amyotrophic lateral sclerosis

et al. 2017

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Mutations in TDP-43 cause amyotrophic lateral sclerosis (ALS), a fatal paralytic disease characterized by degeneration and premature death of motor neurons. The contribution of mutant TDP-43-mediated damage within motor neurons was evaluated using mice expressing a conditional allele of an ALS-causing TDP-43 mutant (Q331K) whose broad expression throughout the central nervous system mimics endogenous TDP-43. TDP-43Q331K mice develop age- and mutant-dependent motor deficits from degeneration and death of motor neurons. Cre-recombinase-mediated excision of the TDP-43Q331K gene from motor neurons is shown to delay onset of motor symptoms and appearance of TDP-43-mediated aberrant nuclear morphology, and abrogate subsequent death of motor neurons. However, reduction of mutant TDP-43 selectively in motor neurons did not prevent age-dependent degeneration of axons and neuromuscular junction loss, nor did it attenuate astrogliosis or microgliosis. Thus, disease mechanism is non-cell autonomous with mutant TDP-43 expressed in motor neurons determining disease onset but progression defined by mutant acting within other cell types.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-017-1698-6) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Mutant TDP-43 within motor neurons drives disease onset but not progression in amyotrophic lateral sclerosis

et al. 2017

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“…For example, dysfunctional nuclear-cytoplasmic transport has emerged as a common mechanistic denominator uniting not only the different clinical conditions, but also various ALS/FTD genes like C9orf72, FUS , and TARDPB. 37-39 …”

Section: Common Pathophysiological Pathways and Mechanisms In Ataxiasmentioning

confidence: 99%

Overcoming the divide between ataxias and spastic paraplegias: Shared phenotypes, genes, and pathways

2017

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Autosomal-dominant spinocerebellar ataxias, autosomal-recessive spinocerebellar ataxias, and hereditary spastic paraplegias have traditionally been designated in separate clinicogenetic disease classifications. This classification system still largely frames clinical thinking and genetic workup in clinical practice. Yet, with the advent of next-generation sequencing, phenotypically unbiased studies have revealed the limitations of this classification system. Various genes (eg, SPG7, SYNE1, PNPLA6) traditionally rooted in either the ataxia or hereditary spastic paraplegia classification system have now been shown to cause ataxia on the one end of the disease continuum and hereditary spastic paraplegia on the other. Other genes such as GBA2 and KIF1C were almost simultaneously published as both a hereditary spastic paraplegia and an ataxia gene. The variability and fluidity of observed phenotypes along the ataxia-spasticity spectrum warrants a rethinking of the traditional classification system. We propose to replace this divisive diagnosis-driven ataxia and hereditary spastic paraplegia classification system by a descriptive, unbiased approach of modular phenotyping. This approach is also open to expansion of the phenotype beyond ataxia and spasticity, which often occur as part of broader multisystem neuronal dysfunction. The concept of a continuous ataxia-spasticity disease spectrum is further supported by ataxias and hereditary spastic paraplegias sharing not only overlapping phenotypes and underlying genes, but also common cellular pathways and disease mechanisms. This suggests a shared vulnerability of cerebellar and corticospinal neurons for common pathophysiological processes. It might be this mechanistic overlap that drives their clinical overlap. A mechanistically inspired classification system will help to pave the way for mechanism-based strategies for drug development.

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“…TDP-43 deposition is possibly mediated by multiple factors, such as impaired protein metabolism, stress granule formation, disrupted RNA metabolism, oxidative stress, neuroinflammation, and toxic factors released from astrocytes [15]. In addition, disrupted nuclear transport is also regarded as an important cause of aggregate formation especially that associated with C9orf72 [16,17]. Among these multiple factors involved in the TDP-43 pathogenesis, increasing lines of evidence support the notion that proteolytic pathways, including proteasome and autophagy systems, play key roles in TDP-43 aggregate formation [4,18–23].…”

Section: Introductionmentioning

confidence: 99%

Formation and spreading of TDP-43 aggregates in cultured neuronal and glial cells demonstrated by time-lapse imaging

et al. 2017

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TAR DNA-binding protein 43 (TDP-43) is a main constituent of cytoplasmic aggregates in neuronal and glial cells in cases of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. We have previously demonstrated that adenovirus-transduced artificial TDP-43 cytoplasmic aggregates formation is enhanced by proteasome inhibition in vitro and in vivo. However, the relationship between cytoplasmic aggregate formation and cell death remains unclear. In the present study, rat neural stem cell lines stably transfected with EGFP- or Sirius-expression vectors under the control of tubulin beta III, glial fibrillary acidic protein, or 2′,3′-cyclic nucleotide 3′-phosphodiesterase promoter were differentiated into neurons, astrocytes, and oligodendrocytes, respectively, in the presence of retinoic acid. The differentiated cells were then transduced with adenoviruses expressing DsRed-tagged human wild type and C-terminal fragment TDP-43 under the condition of proteasome inhibition. Time-lapse imaging analyses revealed growing cytoplasmic aggregates in the transduced neuronal and glial cells, followed by collapse of the cell. The aggregates remained insoluble in culture media, consisted of sarkosyl-insoluble granular materials, and contained phosphorylated TDP-43. Moreover, the released aggregates were incorporated into neighboring neuronal cells, suggesting cell-to-cell spreading. The present study provides a novel tool for analyzing the detailed molecular mechanisms of TDP-43 proteinopathy in vitro.

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Nuclear trafficking in amyotrophic lateral sclerosis and frontotemporal lobar degeneration

Cited by 53 publications

References 121 publications

Mutant TDP-43 within motor neurons drives disease onset but not progression in amyotrophic lateral sclerosis

Mutant TDP-43 within motor neurons drives disease onset but not progression in amyotrophic lateral sclerosis

Overcoming the divide between ataxias and spastic paraplegias: Shared phenotypes, genes, and pathways

Formation and spreading of TDP-43 aggregates in cultured neuronal and glial cells demonstrated by time-lapse imaging

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