Massive transcriptome sequencing of human spinal cord tissues provides new insights into motor neuron degeneration in ALS

D’Erchia, Anna Maria; Gallo, Angela; Manzari, Caterina; Raho, Susanna; Horner, David S.; Chiara, Matteo; Valletti, Alessio; Aiello, Italia; Mastropasqua, Francesca; Ciaccia, Loredana; Locatelli, Franco; Pisani, Francesco; Nicchia, Grazia Paola; Svelto, María; Pesole, Graziano; Picardi, Ernesto

doi:10.1038/s41598-017-10488-7

Cited by 109 publications

(87 citation statements)

References 72 publications

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“…However, the ATP7A M1311V allele frequency is not rare in Ashkenazi Jews (0.01991), whereas it is rare in other ethnic populations (0-0.0003) such as European, Asian, Latino, and African. Because ALS is known to be a multifactorial disease and over 100 genes are intricately involved 29,[56][57][58] , the ATP7A gene may act as one crucial component in an ALS-related network and the ALS disease may be caused by a combination of other disease factors such as genetic defects of other variants in a patient' genome, altered transcripts, and epigenetic and environmental factors together with ATP7A M1311V [59][60][61][62] . In our results of trio-based WGS, the patient had many genetic variants in addition to the variants in ATP7A.…”

Section: Discussionmentioning

confidence: 99%

CRISPR-mediated gene correction links the ATP7A M1311V mutations with amyotrophic lateral sclerosis pathogenesis in one individual

et al. 2020

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Amyotrophic lateral sclerosis (ALS) is a severe disease causing motor neuron death, but a complete cure has not been developed and related genes have not been defined in more than 80% of cases. Here we compared whole genome sequencing results from a male ALS patient and his healthy parents to identify relevant variants, and chose one variant in the X-linked ATP7A gene, M1311V, as a strong disease-linked candidate after profound examination. Although this variant is not rare in the Ashkenazi Jewish population according to results in the genome aggregation database (gnomAD), CRISPR-mediated gene correction of this mutation in patient-derived and re-differentiated motor neurons drastically rescued neuronal activities and functions. These results suggest that the ATP7A M1311V mutation has a potential responsibility for ALS in this patient and might be a potential therapeutic target, revealed here by a personalized medicine strategy.

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Section: Discussionmentioning

confidence: 99%

CRISPR-mediated gene correction links the ATP7A M1311V mutations with amyotrophic lateral sclerosis pathogenesis in one individual

et al. 2020

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“…Raw reads from murine frontal cortex and spinal cord (11)(12)(13), as well as human spinal cord, frontal cortex and cerebellum (11)(12)(13)(14)(15), were downloaded from Gene Expression Omnibus (GEO) with the SRA Toolkit v2.9.2. Reads were trimmed with TrimGalore v0.6.0 using automatic adapter detection and a minimum Phred score of 20.…”

Section: Rna Sequencingmentioning

confidence: 99%

Shortened TDP43 isoforms upregulated by neuronal hyperactivity drive TDP43 pathology in ALS

Weskamp¹,

Tank²,

Miguez³

et al. 2020

Journal of Clinical Investigation

100

101

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“…An extensive body of evidence has suggested that glia contribute to the neurodegeneration observed in ALS and FTD (9,10,(110)(111)(112)(113). Transcriptional assessments and proteomic approaches across the ALS/FTD spectrum have reported robust glia signatures and glia protein modules, respectively, emphasizing a glia involvement in inflammation and contribution to disease (109,(113)(114)(115).…”

Section: Discussionmentioning

confidence: 99%

Cellular and molecular phenotypes ofC9orf72ALS/FTD patient derived iPSC-microglia mono-cultures

Lorenzini

Alsop

Levy

et al. 2020

Preprint

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Background: A mutation in the C9orf72 gene is the most common genetic mutation of familial and sporadic ALS, as well as familial FTD. While prior studies have focused on elucidating the mechanisms of neuronal dysfunction and neurodegeneration associated with this genetic mutation, the contribution of microglia to disease pathogenesis in the ALS/FTD disease spectrum remains poorly understood. Methods: Here, we generated a new disease model consisting of cultured C9orf72 ALS/FTD patient-derived induced pluripotent stem cells differentiated into microglia (iPSC-MG). We used this model to study the intrinsic cellular and molecular phenotypes of microglia triggered by the C9orf72 gene mutation. Results: We show that C9orf72 ALS/FTD iPSC-MG have a similar transcriptional profile compared to control iPSC-MG, despite the presence of C9orf72-associated phenotypes including reduced C9orf72 protein levels and dipeptide-repeat protein translation. Interestingly, C9orf72 ALS/FTD iPSC-MG exhibit intrinsic dysfunction of phagocytic activity upon exposure to Aβ or brain synaptoneurosomes and display a heightened inflammatory response. Detailed analysis of the endosomal and lysosomal pathways revealed altered expression of endosomal marker early endosome antigen 1 and lysosomal associated membrane protein 1 in C9orf72 ALS/FTD iPSC-MG, which was confirmed in patient postmortem tissues. Conclusions: These findings demonstrate that unstimulated C9orf72 iPSC-MG mono-cultures share a largely similar transcriptome profile with control microglia, despite the presence of C9orf72 disease phenotypes. The dysfunction of the endosomal-lysosomal pathway as demonstrated by aberrant microglia phagocytosis and engulfment of cellular debris and brain pathogens suggests that disease-related microglia phenotypes are not intrinsic but instead require microglia to be activated. In summary, the C9orf72 iPSC-MG culture system provides a novel human disease model to study the role of microglia in C9orf72 ALS/FTD disease pathogenesis.

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Massive transcriptome sequencing of human spinal cord tissues provides new insights into motor neuron degeneration in ALS

Cited by 109 publications

References 72 publications

CRISPR-mediated gene correction links the ATP7A M1311V mutations with amyotrophic lateral sclerosis pathogenesis in one individual

CRISPR-mediated gene correction links the ATP7A M1311V mutations with amyotrophic lateral sclerosis pathogenesis in one individual

Shortened TDP43 isoforms upregulated by neuronal hyperactivity drive TDP43 pathology in ALS

Cellular and molecular phenotypes ofC9orf72ALS/FTD patient derived iPSC-microglia mono-cultures

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