Postmortem Cortex Samples Identify Distinct Molecular Subtypes of ALS: Retrotransposon Activation, Oxidative Stress, and Activated Glia

Tam, Oliver H.; Rozhkov, Nikolay V.; Shaw, Regina; Kim, Duyang; Hubbard, Isabel; Fennessey, Samantha; Propp, Nadia; Fagegaltier, Delphine; Ostrow, Lyle W.; Phatnani, Hemali; Ravits, John; Dubnau, Josh; Hammell, Molly

doi:10.1101/574509

Cited by 39 publications

(65 citation statements)

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“…Notably, the IAP-Gag labelling was not uniform, as some neurons expressed higher levels of IAP-Gag and we found clear evidence of ERV-derived protein aggregation (Fig 6d), suggesting that the expression of ERVs in the brain is associated with aggregation of ERV-derived proteins, which could be the underlying reason of the apparent neuroinflammation. and schizophrenia, where an increased expression of TEs has been reported along with the speculation of their contribution to the disease process (Andrews et al, 2000;Douville et al, 2011;Garson et al, 1998;Guo et al, 2018;Jonsson et al, 2020;Karlsson et al, 2001;Li et al, 2015;MacGowan et al, 2007;Perron et al, 1997;Perron et al, 2008;Steele et al, 2005;Sun et al, 2018;Tam et al, 2019b). However, these studies have been difficult to interpret since the clinical observations were correlative and since the modeling of ERV activation in an experimental setting is challenging.…”

Section: Aggregates Of Erv-derived Proteins Are Found In Areas Of Neumentioning

confidence: 99%

“…However, it is becoming increasingly clear that ERVs are aberrantly activated in various human diseases, including a number of neurological disorders. For example, ERV expression has been found to be elevated in the cerebrospinal fluid and in post-mortem brain biopsies from patients with multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease and schizophrenia (Andrews et al, 2000;Douville et al, 2011;Garson et al, 1998;Guo et al, 2018;Karlsson et al, 2001;Li et al, 2015;MacGowan et al, 2007;Perron et al, 1997;Perron et al, 2008;Steele et al, 2005;Sun et al, 2018;Tam et al, 2019b).…”

Section: Introductionmentioning

confidence: 99%

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Activation of endogenous retroviruses during brain development causes neuroinflammation

Jönsson

Garza

Sharma

et al. 2020

Preprint

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AbstractEndogenous retroviruses (ERVs) make up a large fraction of mammalian genomes and are thought to contribute to human disease, including brain disorders. In the brain, aberrant activation of ERVs is a potential trigger for neuroinflammation, but mechanistic insight into this phenomenon remains lacking. Using CRISPR/Cas9-based gene disruption of the epigenetic co-repressor protein Trim28, we found a dynamic H3K9me3-dependent regulation of ERVs in proliferating neural progenitor cells (NPCs), but not in adult neurons. In vivo deletion of Trim28 in cortical NPCs during mouse brain development resulted in viable offspring expressing high levels of ERV expression in excitatory neurons in the adult brain. Neuronal ERV expression was linked to inflammation, including activated microglia, and aggregates of ERV-derived proteins. This study demonstrates that brain development is a critical period for the silencing of ERVs and provides causal in vivo evidence demonstrating that transcriptional activation of ERV in neurons results in neuroinflammation.

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Section: Aggregates Of Erv-derived Proteins Are Found In Areas Of Neumentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Activation of endogenous retroviruses during brain development causes neuroinflammation

Jönsson

Garza

Sharma

et al. 2020

Preprint

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“…They sequenced the RNAs that were bound to TDP-43 protein in human SH-SY5Y neuroblastoma cells using an enhanced crosslinking and immunoprecipitation protocol (eCLIP-seq) (Van Nostrand et al, 2016), and found that transposable elements accounted for 31% of all mapped peaks. Their data support a model whereby human transposons are normally silenced by TDP-43, but that such silencing is reversed in a subset of ALS patients, which may lead to cellular toxicity (Tam et al, 2019).…”

Section: Frontotemporal Lobar Degeneration (Ftld) and Amyotrophic Latmentioning

confidence: 61%

“…The Hammell lab recently analyzed the transcriptomes of 148 ALS cortex tissue samples and identified three ALS clusters based on the observed gene expression profiles: (1) a major cluster of samples with oxidative and proteotoxic stress (61% of patients), (2) a second cluster with glial activation and inflammation (19% of patients) and (3) a third cluster with retrotransposition reactivation (20% of patients) (Tam et al, 2019). Since oxidative stress and inflammation previously have been implicated in ALS, the investigators focused on the retrotransposon cluster, which included elements from the LINE, SINE, and LTR classes.…”

Section: Frontotemporal Lobar Degeneration (Ftld) and Amyotrophic Latmentioning

confidence: 99%

Aberrantly High Levels of Somatic LINE-1 Expression and Retrotransposition in Human Neurological Disorders

Terry

Devine

2020

Front. Genet.

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Retrotransposable elements (RTEs) have actively multiplied over the past 80 million years of primate evolution, and as a consequence, such elements collectively occupy ~ 40% of the human genome. As RTE activity can have detrimental effects on the human genome and transcriptome, silencing mechanisms have evolved to restrict retrotransposition. The brain is the only known somatic tissue where RTEs are de-repressed throughout the life of a healthy human and each neuron in specific brain regions accumulates up to ~13.7 new somatic L1 insertions (and perhaps more). However, even higher levels of somatic RTE expression and retrotransposition have been found in a number of human neurological disorders. This review is focused on how RTE expression and retrotransposition in neuronal tissues might contribute to the initiation and progression of these disorders. These disorders are discussed in three broad and sometimes overlapping categories: 1) disorders such as Rett syndrome, Aicardi-Goutières syndrome, and ataxia-telangiectasia, where expression/retrotransposition is increased due to mutations in genes that play a role in regulating RTEs in healthy cells, 2) disorders such as autism spectrum disorder, schizophrenia, and substance abuse disorders, which are thought to be caused by a combination of genetic and environmental stress factors, and 3) disorders associated with age, such as frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), and normal aging, where there is a time-dependent accumulation of neurological degeneration, RTE copy number, and phenotypes. Research has revealed increased levels of RTE activity in many neurological disorders, but in most cases, a clear causal link between RTE activity and these disorders has not been well established. At the same time, even if increased RTE activity is a passenger and not a driver of disease, a detrimental effect is more likely than a beneficial one. Thus, a better understanding of the role of RTEs in neuronal tissues likely is an important part of understanding, preventing, and treating these disorders.

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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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Postmortem Cortex Samples Identify Distinct Molecular Subtypes of ALS: Retrotransposon Activation, Oxidative Stress, and Activated Glia

Cited by 39 publications

References 56 publications

Activation of endogenous retroviruses during brain development causes neuroinflammation

Activation of endogenous retroviruses during brain development causes neuroinflammation

Aberrantly High Levels of Somatic LINE-1 Expression and Retrotransposition in Human Neurological Disorders

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

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