C9orf72 deficiency promotes microglial-mediated synaptic loss in aging and amyloid accumulation

Lall, Deepti; Lorenzini, Ileana; Mota, Thomas A.; Bell, Shaughn; Mahan, Thomas E.; Ulrich, Jason D.; Davtyan, Hayk; Rexach, Jessica E.; Muhammad, A.K.M. Ghulam; Shelest, Oksana; Landeros, Jesse; Vázquez, M. Eugenio; Kim, Junwon; Ghaffari, Layla T.; O’Rourke, Jacqueline G.; Geschwind, Daniel H.; Blurton‐Jones, Mathew; Holtzman, David M.; Sattler, Rita; Baloh, Robert H.

doi:10.1016/j.neuron.2021.05.020

Cited by 89 publications

(82 citation statements)

References 95 publications

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“…C9orf72 is widely expressed by myeloid cells, including microglia (Rizzu et al, 2016). A deficit of C9orf72 altered the homeostatic gene signature of microglia while C9orf72-deficient microglia promote synaptic loss and behavioral defects in mice (Lall et al, 2021). Using the largest set of summary statistics from Parkinson's disease (PD) GWAS a recent study showed significant enrichment of PD risk heritability in open chromatin regions of microglia and monocytes, supporting the importance of these cells in PD pathogenesis (Andersen et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

Microglia in Neuroinflammation and Neurodegeneration: From Understanding to Therapy

2021

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Microglia are the resident macrophages of the central nervous system (CNS) acting as the first line of defense in the brain by phagocytosing harmful pathogens and cellular debris. Microglia emerge from early erythromyeloid progenitors of the yolk sac and enter the developing brain before the establishment of a fully mature blood–brain barrier. In physiological conditions, during brain development, microglia contribute to CNS homeostasis by supporting cell proliferation of neural precursors. In post-natal life, such cells contribute to preserving the integrity of neuronal circuits by sculpting synapses. After a CNS injury, microglia change their morphology and down-regulate those genes supporting homeostatic functions. However, it is still unclear whether such changes are accompanied by molecular and functional modifications that might contribute to the pathological process. While comprehensive transcriptome analyses at the single-cell level have identified specific gene perturbations occurring in the “pathological” microglia, still the precise protective/detrimental role of microglia in neurological disorders is far from being fully elucidated. In this review, the results so far obtained regarding the role of microglia in neurodegenerative disorders will be discussed. There is solid and sound evidence suggesting that regulating microglia functions during disease pathology might represent a strategy to develop future therapies aimed at counteracting brain degeneration in multiple sclerosis, Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis.

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Section: Introductionmentioning

confidence: 99%

Microglia in Neuroinflammation and Neurodegeneration: From Understanding to Therapy

2021

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“…Indeed, C9orf72 -/- peripheral myeloid cells have been demonstrated to have hyperactive type I interferon responses, mediated by impaired lysosomal degradation of the stimulator of interferon genes (STING) protein[38], thus suggesting that loss of normal C9orf72 function may lead to a proinflammatory state, as we observed in our data. Similarly, mouse C9orf72 -/- microglia have also been shown to have higher levels of STING protein and increased expression of interferon response genes as well as other activation response genes[32]. Qualitative pathological assessment has shown signs of increased microglial activation in C9orf72 HRE post mortem tissue[18], and microglial activation in the cervical corticospinal tract has been shown to correlate with disease progression[11].…”

Section: Resultsmentioning

confidence: 99%

Random forest modelling of neuropathological features identifies microglial activation as an accurate pathological classifier of C9orf72-related amyotrophic lateral sclerosis

Rifai¹,

Longden²,

O’Shaughnessy³

et al. 2021

Preprint

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Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are regarded as two ends of a pathogenetic spectrum, termed ALS-frontotemporal spectrum disorder (ALS-FTSD). However, it is currently difficult to predict where on the spectrum an individual will lie, especially for patients with C9orf72 hexanucleotide repeat expansions (HRE), a mutation associated with both ALS and FTD. It has been shown that both inflammation and protein misfolding influence aspects of ALS and ALS-FTSD disease pathogenesis, such as the manifestation or severity of motor or cognitive symptoms. Previous studies have highlighted markers which may influence C9orf72-associated disease presentation in a targeted fashion, though there has yet to be a systematic and quantitative assessment of common immunohistochemical markers to investigate the significance of these pathways in an unbiased manner. Here we report the first extensive digital pathological assessment with random forest modelling of pathological markers often used in neuropathology practice. This study profiles glial activation and protein misfolding in a cohort of deeply clinically profiled post-mortem tissue from patients with a C9orf72 HRE, who either met the criteria for a diagnosis of ALS or ALS-FTSD. We show that microglial immunohistochemical staining features, both morphological and spatial, are the best independent classifiers of disease status and that clinicopathological associations exist between microglial activation status and cognitive dysfunction in ALS-FTSD patients with C9orf72 HRE. Furthermore, we show that spatially resolved changes in FUS staining are also an accurate predictor of disease status, implying that liquid-liquid phase shift of this aggregation-prone RNA-binding protein may be important in ALS caused by a C9orf72 HRE. Our findings provide further support to the hypothesis of dysfunctional immune regulation and proteostasis in the pathogenesis of C9orf72 ALS and provide a framework for digital analysis of commonly used neuropathological stains as a tool to enrich our understanding of clinicopathological associations between cohorts.

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“…Furthermore, consistent with increasing reports of C9ORF72 localization at the synapse ( Frick et al, 2018 ; Xiao et al, 2019 ), hippocampal regions of 3-month old C9ORF72 knockout mice show a reduction in synaptic density ( Xiao et al, 2019 ), suggesting that haploinsufficiency may play a role in cortical synaptic loss. C9ORF72 is also highly expressed in microglia ( Rizzu et al, 2016 ), and recent work has determined that loss of C9ORF72 exacerbates microglial synaptic pruning activity in the cortex, which correlates with cognitive impairments ( Lall et al, 2021 ). Synaptic loss may therefore be driven by perturbed microglial function driven through C9ORF72 haploinsufficiency.…”

Section: Cortical Dysfunction In C9orf72 Repeat Expansion-mediated Amyotrophic Lateral Sclerosis-frontotemporal Dementmentioning

confidence: 99%

“…Synaptic loss was found to correlate with cognitive decline (Henstridge et al, 2018;Lall et al, 2021).…”

Section: Post-symptomatic Cortical Neurophysiological Functionmentioning

confidence: 99%

Emerging Mechanisms Underpinning Neurophysiological Impairments in C9ORF72 Repeat Expansion-Mediated Amyotrophic Lateral Sclerosis/Frontotemporal Dementia

Pasniceanu

Atwal

Souza

et al. 2021

Front. Cell. Neurosci.

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Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are characterized by degeneration of upper and lower motor neurons and neurons of the prefrontal cortex. The emergence of the C9ORF72 hexanucleotide repeat expansion mutation as the leading genetic cause of ALS and FTD has led to a progressive understanding of the multiple cellular pathways leading to neuronal degeneration. Disturbances in neuronal function represent a major subset of these mechanisms and because such functional perturbations precede degeneration, it is likely that impaired neuronal function in ALS/FTD plays an active role in pathogenesis. This is supported by the fact that ALS/FTD patients consistently present with neurophysiological impairments prior to any apparent degeneration. In this review we summarize how the discovery of the C9ORF72 repeat expansion mutation has contributed to the current understanding of neuronal dysfunction in ALS/FTD. Here, we discuss the impact of the repeat expansion on neuronal function in relation to intrinsic excitability, synaptic, network and ion channel properties, highlighting evidence of conserved and divergent pathophysiological impacts between cortical and motor neurons and the influence of non-neuronal cells. We further highlight the emerging association between these dysfunctional properties with molecular mechanisms of the C9ORF72 mutation that appear to include roles for both, haploinsufficiency of the C9ORF72 protein and aberrantly generated dipeptide repeat protein species. Finally, we suggest that relating key pathological observations in C9ORF72 repeat expansion ALS/FTD patients to the mechanistic impact of the C9ORF72 repeat expansion on neuronal function will lead to an improved understanding of how neurophysiological dysfunction impacts upon pathogenesis.

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C9orf72 deficiency promotes microglial-mediated synaptic loss in aging and amyloid accumulation

Cited by 89 publications

References 95 publications

Microglia in Neuroinflammation and Neurodegeneration: From Understanding to Therapy

Microglia in Neuroinflammation and Neurodegeneration: From Understanding to Therapy

Random forest modelling of neuropathological features identifies microglial activation as an accurate pathological classifier of C9orf72-related amyotrophic lateral sclerosis

Emerging Mechanisms Underpinning Neurophysiological Impairments in C9ORF72 Repeat Expansion-Mediated Amyotrophic Lateral Sclerosis/Frontotemporal Dementia

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