C9orf72 and RAB7L1 regulate vesicle trafficking in amyotrophic lateral sclerosis and frontotemporal dementia

Aoki, Yosuke; Manzano, Raquel; Lee, Yi; Dafinca, Ruxandra; Aoki, Misako; Douglas, Andrew G.L.; Varela, Miguel A.; Sathyaprakash, Chaitra; Scaber, Jakub; Barbagallo, Paola; Vader, Pieter; Mäger, Imre; Ezzat, Kariem; Turner, Martin R; Ito, Naoki; Gasco, Samanta; Ohbayashi, Norihiko; Andaloussi, Samir El; Takeda, Shin’ichi; Fukuda, Mitsunori; Talbot, Kevin; Wood, Matthew

doi:10.1093/brain/awx024

Cited by 135 publications

(151 citation statements)

References 33 publications

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“…4a, 5b). While previous studies have linked low C9ORF72 levels to changes in vesicle trafficking or autophagy 18,20,30–33 , it remains unknown if loss of C9ORF72 protein directly contributes to degeneration. Thus, we re-expressed C9ORF72 (isoform A or B) in iMNs using a retroviral cassette (Supplementary Fig.…”

Section: C9orf72 Is Haploinsufficient In Alsmentioning

confidence: 98%

“…There are conflicting reports as to whether C9ORF72 levels affect endosomes or lysosomes more significantly, and whether C9ORF72 levels affect vesicle trafficking in neurons in the same way as in cell lines 18,30–33,38,39 . In addition, the functional role of C9ORF72 in patient motor neurons is unclear.…”

Section: Reduced C9orf72 Activity Disrupts Lysosomal Biogenesis In Momentioning

confidence: 99%

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Haploinsufficiency leads to neurodegeneration in C9ORF72 ALS/FTD human induced motor neurons

Shi

Lin

Staats

et al. 2018

Nat Med

495

551

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Summary An intronic GGGGCC repeat expansion in C9ORF72 is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), but its pathogenic mechanism remains unclear. Here we use human induced motor neurons (iMNs) to show that repeat-expanded C9ORF72 is haploinsufficient in ALS. We show that C9ORF72 interacts with endosomes and is required for normal vesicle trafficking and lysosomal biogenesis in motor neurons. Repeat expansion reduces C9ORF72 expression, triggering neurodegeneration through two mechanisms: accumulation of glutamate receptors leading to excitotoxicity, and impaired clearance of neurotoxic dipeptide repeat proteins derived from the repeat expansion. Thus, cooperativity between gain- and loss-of-function mechanisms leads to neurodegeneration. Restoring C9ORF72 levels or augmenting its function with constitutively active RAB5 or chemical modulators of RAB5 effectors rescues patient neuron survival and ameliorates neurodegenerative processes in both gain- and loss-of function C9ORF72 mouse models. Thus, modulating vesicle trafficking can rescue neurodegeneration caused by the C9ORF72 repeat expansion. Coupled with rare mutations in ALS2, FIG4, CHMP2B, OPTN, and SQSTM1, our results reveal mechanistic convergence on vesicle trafficking in ALS/FTD.

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Section: C9orf72 Is Haploinsufficient In Alsmentioning

confidence: 98%

Section: Reduced C9orf72 Activity Disrupts Lysosomal Biogenesis In Momentioning

confidence: 99%

Haploinsufficiency leads to neurodegeneration in C9ORF72 ALS/FTD human induced motor neurons

Shi

Lin

Staats

et al. 2018

Nat Med

495

551

View full text Add to dashboard Cite

show abstract

“…C9orf72 KO mice show accumulation of the p62 and LC3 proteins pointing to an impairment of autophagy (Sullivan et al, 2016). Fibroblasts derived from patients with mutations in C9orf72 have a lower number of endosomes and an altered expression patern of the mannose 6-phosphate receptor (Aoki et al, 2017) Fibroblasts from patients with mutations in the C9orf72 gene secrete fewer extracellular vesicles (Aoki et al, 2017) TA B L E 1 (Continued)…”

Section: Effect Of the Coded Protein On The Biogenesis/secretion/compmentioning

confidence: 99%

The interplay between aging‐associated loss of protein homeostasis and extracellular vesicles in neurodegeneration

Guix

2019

J of Neuroscience Research

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The finding of an effective cure or treatment for neurodegenerative diseases is one of the biggest challenges for this century. Although these diseases show different clinical manifestations, the presence of toxic protein aggregates in the brain of patients is a common feature to all of them, suggesting a loss of protein homeostasis.Aging, the primary risk factor for the majority of neurodegenerative disorders, is linked to the impairment of degradative compartments such as lysosomes and autophagosomes. Besides, many genetic factors for Alzheimer's disease, Parkinson's disease, or frontotemporal dementia, as examples of frequent neurodegenerative diseases, are causative of endo-lysosomal and autophagosomal dysfunctions. There is scientific evidence suggesting that neurons can counteract the accumulation of undegraded cellular material by the secretion of extracellular vesicles (EVs), which are vesicles with a size ranging from 50 to 100 nm generated in a type of endosomal compartment named multivesicular body. EVs play a crucial role in removing cellular waste, promoting protein aggregation, and spreading toxic protein aggregates in the brain of patients. In this review, the interplay between the impairment of degradative compartments, the secretion of EVs, and their pathological/beneficial role in neurodegeneration is described.

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“…Current evidence shows that RBPs involved in splicing, such as hnRNPs and the SR splicing factors that comprise the spliceosome, are sequestered by mutant repeat-containing RNA (Cooper-Knock et al, 2014; Lee et al, 2013) (see ). Additionally, the repeat expansion, which normally regulates vesicle trafficking and autophagy (Yang et al 2016; Aoki et al 2017). can interfere with transcription of the C9orf72 gene, resulting in haploinsufficiency of the protein product (Burberry et al, 2016; Ciura et al, 2013; DeJesus-Hernandez et al, 2011).…”

Section: Rbp Sequestration By Microsatellite Repeat Expansionsmentioning

confidence: 99%

RNA metabolism in neurodegenerative disease

Liu

Cali

Lee

2017

Disease Models &Amp; Mechanisms

115

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Aging-related neurodegenerative diseases are progressive and fatal neurological diseases that are characterized by irreversible neuron loss and gliosis. With a growing population of aging individuals, there is a pressing need to better understand the basic biology underlying these diseases. Although diverse disease mechanisms have been implicated in neurodegeneration, a common theme of altered RNA processing has emerged as a unifying contributing factor to neurodegenerative disease. RNA processing includes a series of distinct processes, including RNA splicing, transport and stability, as well as the biogenesis of non-coding RNAs. Here, we highlight how some of these mechanisms are altered in neurodegenerative disease, including the mislocalization of RNA-binding proteins and their sequestration induced by microsatellite repeats, microRNA biogenesis alterations and defective tRNA biogenesis, as well as changes to long-intergenic non-coding RNAs. We also highlight potential therapeutic interventions for each of these mechanisms.

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C9orf72 and RAB7L1 regulate vesicle trafficking in amyotrophic lateral sclerosis and frontotemporal dementia

Cited by 135 publications

References 33 publications

Haploinsufficiency leads to neurodegeneration in C9ORF72 ALS/FTD human induced motor neurons

Haploinsufficiency leads to neurodegeneration in C9ORF72 ALS/FTD human induced motor neurons

The interplay between aging‐associated loss of protein homeostasis and extracellular vesicles in neurodegeneration

RNA metabolism in neurodegenerative disease

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