Lost in Transportation: Nucleocytoplasmic Transport Defects in ALS and Other Neurodegenerative Diseases

Kim, Hong Joo; Taylor, J. Paul

doi:10.1016/j.neuron.2017.07.029

Cited by 235 publications

(206 citation statements)

References 113 publications

(163 reference statements)

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“…Since TDP-43 pathology has been attributed to nuclear membrane defects and problems with nucleocytoplasmic transport system [13, 35], we first investigated the nuclear membrane of Betz cells in both control and TDP-43 cases. Nuclear membranes of Betz cells in normal controls were almost perfect circle and no defects were observed (Fig.…”

Section: Resultsmentioning

confidence: 99%

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Mitochondria, ER, and nuclear membrane defects reveal early mechanisms for upper motor neuron vulnerability with respect to TDP-43 pathology

et al. 2018

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Insoluble aggregates containing TDP-43 are widely observed in the diseased brain, and defined as “TDP-43 pathology” in a spectrum of neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), Alzheimer’s disease and ALS with frontotemporal dementia. Here we report that Betz cells of patients with TDP-43 pathology display a distinct set of intracellular defects especially at the site of nuclear membrane, mitochondria and endoplasmic reticulum (ER). Numerous TDP-43 mouse models have been generated to discern the cellular and molecular basis of the disease, but mechanisms of neuronal vulnerability remain unknown. In an effort to define the underlying causes of corticospinal motor neuron (CSMN) degeneration, we generated and characterized a novel CSMN reporter line with TDP-43 pathology, the prp-TDP-43A315T-UeGFP mice. We find that TDP-43 pathology related intracellular problems emerge very early in the disease. The Betz cells in humans and CSMN in mice both have impaired mitochondria, and display nuclear membrane and ER defects with respect to TDP-43 pathology.

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Section: Resultsmentioning

confidence: 99%

“…Defects in nucleo-cytoplasmic shuttling of macromolecules have been suggested as a major phenomenon in ALS [35]. TDP-43 aggregates were found to sequester proteins involved in nuclear import of proteins and nuclear export of RNA, causing major imbalance in nucleo-cytoplasmic transport of biomolecules [13].…”

Section: Discussionmentioning

confidence: 99%

Mitochondria, ER, and nuclear membrane defects reveal early mechanisms for upper motor neuron vulnerability with respect to TDP-43 pathology

et al. 2018

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“…This view proposes that the more soluble protofibrillar or oligomeric aggregates (as opposed to the more mature fibrillar aggregates formed inside the nucleus) have toxic properties in afflicted neurons [14–18]. Whether or not the nuclear inclusion bodies are the major source of nuclear protein toxicity, nuclear dysfunctions such as transcriptional alteration and impaired nucleocytoplasmic transport are evident in many cases of neurodegenerative diseases [19, 20]. …”

Section: Protein Toxicity In the Nucleusmentioning

confidence: 99%

“…The mechanisms by which nucleocytoplasmic transport becomes disrupted range from sequestration of nuclear pore complex (NPC) molecules by toxic RNA or proteins [19, 51–56] to direct blockage of nuclear pores by toxic disease proteins [57]. Some excellent reviews on this topic have recently been published, which we recommend for detailed discussion [19, 50]. …”

Section: Protein Toxicity In the Nucleusmentioning

confidence: 99%

Mechanisms of protein toxicity in neurodegenerative diseases

Chung

Lee

2018

Cell. Mol. Life Sci.

120

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Protein toxicity can be defined as all the pathological changes that ensue from accumulation, mis-localization, and/or multimerization of disease-specific proteins. Most neurodegenerative diseases manifest protein toxicity as one of their key pathogenic mechanisms, the details of which remain unclear. By systematically deconstructing the nature of toxic proteins, we aim to elucidate and illuminate some of the key mechanisms of protein toxicity from which therapeutic insights may be drawn. In this review, we focus specifically on protein toxicity from the point of view of various cellular compartments such as the nucleus and the mitochondria. We also discuss the cell-to-cell propagation of toxic disease proteins that complicates the mechanistic understanding of the disease progression as well as the spatiotemporal point at which to therapeutically intervene. Finally, we discuss selective neuronal vulnerability, which still remains largely enigmatic.

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“…Data from model systems implicate poly-GA [63] and poly-PR [8, 60, 132] DPRs, as well as the GGGGCC repeat expansion itself [37, 170], in producing nucleocytoplasmic transport defects; these and other model-based studies have been reviewed in detail elsewhere [65, 113]. iPSC-derived neurons from patients with C9orf72 -ALS show evidence of nucleocytoplasmic defects, with decreased nuclear/cytoplasmic Ran ratio [170] and decreased nuclear RCC1/RanGEF [60], as well as large RanGAP1-positive puncta that occasionally co-localize with RNA foci [170].…”

Section: Clinical and Anatomical Features Of C9orf72-ftd/alsmentioning

confidence: 99%

C9orf72-FTD/ALS pathogenesis: evidence from human neuropathological studies

et al. 2018

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What are the most important and treatable pathogenic mechanisms in C9orf72-FTD/ALS? Model-based efforts to address this question are forging ahead at a blistering pace, often with conflicting results. But what does the human neuropathological literature reveal? Here, we provide a critical review of the human studies to date, seeking to highlight key gaps or uncertainties in our knowledge. First, we engage the C9orf72-specific mechanisms, including C9orf72 haploinsufficiency, repeat RNA foci, and dipeptide repeat protein inclusions. We then turn to some of the most prominent C9orf72-associated features, such as TDP-43 loss-of-function, TDP-43 aggregation, and nuclear transport defects. Finally, we review potential disease-modifying epigenetic and genetic factors and the natural history of the disease across the lifespan. Throughout, we emphasize the importance of anatomical precision when studying how candidate mechanisms relate to neuronal, regional, and behavioral findings. We further highlight methodological approaches that may help address lingering knowledge gaps and uncertainties, as well as other logical next steps for the field. We conclude that anatomically oriented human neuropathological studies have a critical role to play in guiding this fast-moving field toward effective new therapies.

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Lost in Transportation: Nucleocytoplasmic Transport Defects in ALS and Other Neurodegenerative Diseases

Cited by 235 publications

References 113 publications

Mitochondria, ER, and nuclear membrane defects reveal early mechanisms for upper motor neuron vulnerability with respect to TDP-43 pathology

Mitochondria, ER, and nuclear membrane defects reveal early mechanisms for upper motor neuron vulnerability with respect to TDP-43 pathology

Mechanisms of protein toxicity in neurodegenerative diseases

C9orf72-FTD/ALS pathogenesis: evidence from human neuropathological studies

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