Synaptopathy Mechanisms in ALS Caused by C9orf72 Repeat Expansion

Nishimura, Agnes L.; Arias, Natalia

doi:10.3389/fncel.2021.660693

Cited by 9 publications

(9 citation statements)

References 185 publications

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“…48% of these TDP-43 cytoplasmic accumulations were also positive for p62 ( Supplementary Figure 2B ). Synaptic impairment is also an important pathological mechanism is FTD/ALS and both gain and loss of function mechanisms of the C9ORF72 mutation can lead to synapse loss in a diversity of models ( Choi et al, 2019 ; Lall et al, 2021 ; Nishimura and Arias, 2021 ; Huber et al, 2022a , b ). We measured the density of the synaptic marker Synaptic Vesicle Protein 2 (SV2) in the frontal and motor cortices of the C9ORF72 deficient mice and observed that it was markedly decreased relatively to control animals ( Figures 3E, F ).…”

Section: Resultsmentioning

confidence: 99%

C9ORF72 knockdown triggers FTD-like symptoms and cell pathology in mice

Lopez-Herdoiza

Bauché

Wilmet

et al. 2023

Front. Cell. Neurosci.

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The GGGGCC intronic repeat expansion within C9ORF72 is the most common genetic cause of ALS and FTD. This mutation results in toxic gain of function through accumulation of expanded RNA foci and aggregation of abnormally translated dipeptide repeat proteins, as well as loss of function due to impaired transcription of C9ORF72. A number of in vivo and in vitro models of gain and loss of function effects have suggested that both mechanisms synergize to cause the disease. However, the contribution of the loss of function mechanism remains poorly understood. We have generated C9ORF72 knockdown mice to mimic C9-FTD/ALS patients haploinsufficiency and investigate the role of this loss of function in the pathogenesis. We found that decreasing C9ORF72 leads to anomalies of the autophagy/lysosomal pathway, cytoplasmic accumulation of TDP-43 and decreased synaptic density in the cortex. Knockdown mice also developed FTD-like behavioral deficits and mild motor phenotypes at a later stage. These findings show that C9ORF72 partial loss of function contributes to the damaging events leading to C9-FTD/ALS.

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Section: Resultsmentioning

confidence: 99%

C9ORF72 knockdown triggers FTD-like symptoms and cell pathology in mice

Lopez-Herdoiza

Bauché

Wilmet

et al. 2023

Front. Cell. Neurosci.

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“…In addition to serving a role in cell-type-specific toxicity via accumulation of sense and antisense RNAs or dipeptide repeat proteins, C9orf72 genetic expansion also leads to a loss of function of c9orf72 protein (Donnelly et al, 2013;Gitler and Tsuiji, 2016;Balendra and Isaacs, 2018;Serio and Patani, 2018;Zhang et al, 2019;Cook et al, 2020;Zhu et al, 2020;Maor-Nof et al, 2021). Intriguingly, being essential for normal vesicle trafficking through interaction with Rab GTPase, c9orf72 controls the level of postsynaptic receptors, and its dysfunction can lead to synaptic pathology (Shi et al, 2018;Levine et al, 2013;Xiao et al, 2019;Starr and Sattler, 2018;Nishimura and Arias, 2021). We therefore next considered the impact of C9orf72 expansion on synaptic inputs to L5-PYRs in acute M1 slices (Figures 2E-2G).…”

Section: Behavioral Screening In Young C9-500 Female Micementioning

confidence: 99%

Enhanced motor cortex output and disinhibition in asymptomatic female mice with C9orf72 genetic expansion

Amalyan¹,

Tamboli²,

Lazarevich³

et al. 2022

Cell Reports

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“…Distinct pathologic mechanisms have been hypothesized for G 4 C 2 expansion, including: (1) a loss-of-function due to haploinsufficiency of C9ORF72 protein expression; (2) a gain-of-function of the repeat RNA aggregates or RNA foci; and (3) aggregation of dipeptide repeats (DPRs), which are transcribed from G 4 C 2 RNA repeats by repeat-associated non-ATG-initiated (RAN) translation (Ash et al, 2013 ; Mori et al, 2013 ; Mizielinska and Isaacs, 2014 ). Several metabolic, proteostasis and neuronal processes are known to be impaired in C9ORF72 -mediated pathogenesis, including autophagy, lysosomal function, ubiquitin-proteasome system (UPS), unfolded protein response (UPR) and axonal transport (Alhindi et al, 2021 ; Nishimura and Arias, 2021 ; Smeyers et al, 2021 ), all of which are shown to be critical for cellular health, but also for the organization, structure, strength and function of the synapse.…”

Section: Als/ftd Models Of Diseasementioning

confidence: 99%

Synaptic dysfunction in ALS and FTD: anatomical and molecular changes provide insights into mechanisms of disease

Gelon

Dutchak

Sephton

2022

Front. Mol. Neurosci.

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Synaptic loss is a pathological feature of all neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). ALS is a disease of the cortical and spinal motor neurons resulting in fatal paralysis due to denervation of muscles. FTD is a form of dementia that primarily affects brain regions controlling cognition, language and behavior. Once classified as two distinct diseases, ALS and FTD are now considered as part of a common disease spectrum based on overlapping clinical, pathological and genetic evidence. At the cellular level, aggregation of common proteins and overlapping gene susceptibilities are shared in both ALS and FTD. Despite the convergence of these two fields of research, the underlying disease mechanisms remain elusive. However, recent discovers from ALS and FTD patient studies and models of ALS/FTD strongly suggests that synaptic dysfunction is an early event in the disease process and a unifying hallmark of these diseases. This review provides a summary of the reported anatomical and cellular changes that occur in cortical and spinal motor neurons in ALS and FTD tissues and models of disease. We also highlight studies that identify changes in the proteome and transcriptome of ALS and FTD models and provide a conceptual overview of the processes that contribute to synaptic dysfunction in these diseases. Due to space limitations and the vast number of publications in the ALS and FTD fields, many articles have not been discussed in this review. As such, this review focuses on the three most common shared mutations in ALS and FTD, the hexanucleuotide repeat expansion within intron 1 of chromosome 9 open reading frame 72 (C9ORF72), transactive response DNA binding protein 43 (TARDBP or TDP-43) and fused in sarcoma (FUS), with the intention of highlighting common pathways that promote synaptic dysfunction in the ALS-FTD disease spectrum.

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Synaptopathy Mechanisms in ALS Caused by C9orf72 Repeat Expansion

Cited by 9 publications

References 185 publications

C9ORF72 knockdown triggers FTD-like symptoms and cell pathology in mice

C9ORF72 knockdown triggers FTD-like symptoms and cell pathology in mice

Enhanced motor cortex output and disinhibition in asymptomatic female mice with C9orf72 genetic expansion

Synaptic dysfunction in ALS and FTD: anatomical and molecular changes provide insights into mechanisms of disease

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