Monocytes of patients with amyotrophic lateral sclerosis linked to gene mutations display altered TDP‐43 subcellular distribution

Marco, Giovanni De; Lomartire, Annarosa; Calvo, Andrea; Risso, Alessandra; Luca, Elisa De; Mostert, M.; Mandrioli, Jessica; Caponnetto, Claudia; Borghero, Giuseppe; Manera, Umberto; Canosa, Antonio; Moglia, Cristina; Restagno, Gabriella; Fini, Nicola; Tarella, Corrado; Giordana, Maria Teresa; Rinaudo, M.; Chiò, Adriano

doi:10.1111/nan.12328

Cited by 26 publications

(16 citation statements)

References 85 publications

(153 reference statements)

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“…Interestingly, our study revealed that ALS MDMi recapitulated de novo TDP-43 aggregates and increased phospho-TDP-43 immunoreactivity, which are major hallmarks of ALS. These observations further support the growing evidence for TDP-43 pathology in microglia (Paolicelli et al, 2017), and other non-neuronal cell types including skin fibroblasts (Riancho et al, 2020), circulating lymphomonocytes, and in monocytes/macrophages from a subgroup of ALS patients (De Marco et al, 2017; De Marco et al, 2011). Our study is the first to report the appearance of abnormal TDP-43 pathology in microglia generated from people living with ALS.…”

Section: Discussionsupporting

confidence: 82%

ALS monocyte-derived microglia reveal cytoplasmic TDP-43 accumulation, DNA damage, and cell-specific impairment of phagocytosis associated with disease progression

Quek

Cuní-López

Stewart

et al. 2020

Preprint

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Aims: Amyotrophic lateral sclerosis (ALS) is a multifactorial neurodegenerative disease characterised by the loss of upper and lower motor neurons. Neuroinflammation mediated by microglial activation is evident in post-mortem brain tissues, and in brain imaging of patients with ALS. However, the exact role of microglia in ALS remains to be elucidated partly due to the lack of an accurate microglial model system that is able to recapitulate the clinical pathology of ALS. Moreover, direct sampling of microglia from patients with ALS is not feasible, further limiting the study of microglial function in ALS. To address this shortcoming, we describe an approach that generates monocyte-derived microglia (MDMi) that are capable of expressing molecular markers, and functional characteristics similar to resident human brain microglia. Importantly, MDMi can be routinely and reproducibly generated from ALS patient blood, and reveal patient heterogeneity associated with age, sex and disease subgroup. Methods: MDMi were successfully established from all 30 ALS patients, including 15 patients with slow disease progression, 6 with intermediate progression, and 9 with rapid progression, together with 20 non-affected heathy controls (HC). Results: Our ALS MDMi model recapitulated canonical pathological features of ALS including non-phosphorylated and phosphorylated-TDP-43-positive pathological inclusions. We further observed significantly impaired phagocytosis, altered cytokine expression and microglial morphology, as well as elevated DNA damage in ALS compared to HC MDMi. Abnormal phagocytosis was observed in all ALS cases, and was correlated to the progression of disease. Moreover, in-depth analysis of individual microglia revealed cell-specific variation in phagocytic function that was significantly altered, and exacerbated in rapid disease progression. Conclusions: Our approach enabled us to generate ALS patient microglia from peripheral blood samples using a rapid, robust, cost-effective, and reproducible protocol. We have shown that ALS monocyte-derived microglia have significantly altered functional behaviour compared to age-matched HCs, with a major deficit in phagocytic activity. This is also the first demonstration of abnormal TDP-43 localisation in microglia grown from ALS patients. Overall, this approach is highly applicable to monitor disease progression and can be applied as a functional readout in clinical trials for anti-neuroinflammatory agents. Additionally, this model system can be used as a basis for personalised therapeutic treatment for ALS, as well as other neurodegenerative diseases.

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Section: Discussionsupporting

confidence: 82%

ALS monocyte-derived microglia reveal cytoplasmic TDP-43 accumulation, DNA damage, and cell-specific impairment of phagocytosis associated with disease progression

Quek

Cuní-López

Stewart

et al. 2020

Preprint

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“…Further evidence of TDP-43 spreading comes from the higher levels of free and exosomal TDP-43 identified in the CSF of ALS patients compared to control groups (Kasai et al , 2009; Sproviero et al , 2018). TDP-43 aggregates were also discovered in serum leucocytes from ALS patients (Foulds et al , 2008, 2009; Corrado et al , 2009; De Marco et al , 2011, 2017; Verstraete et al , 2012; Alquezar et al , 2016). Although pathological TDP-43 has the property to penetrate nearby cells, it remains unclear as to how this phenomenon occurs.…”

Section: The Prion-like Characteristics Of Aggregated Tdp-43mentioning

confidence: 90%

The debated toxic role of aggregated TDP-43 in amyotrophic lateral sclerosis: a resolution in sight?

Hergesheimer

Chami

Assis

et al. 2019

Brain

146

141

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“…There is now evidence of abnormal accumulation/location of these proteins in monocytes. For example, altered location of TDP43 in monocytes of patients with genetic mutations in TARDBP, the gene encoding TDP-43 has been demonstrated (111). There is also a report that C9orf72 is expressed in myeloid cells and that expression in monocytes increases after activation (112).…”

Section: Monocyte Numbers and Proportionsmentioning

confidence: 99%

The Peripheral Immune System and Amyotrophic Lateral Sclerosis

et al. 2020

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Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease that is defined by loss of upper and lower motor neurons, associated with accumulation of protein aggregates in cells. There is also pathology in extra-motor areas of the brain, Possible causes of cell death include failure to deal with the aggregated proteins, glutamate toxicity and mitochondrial failure. ALS also involves abnormalities of metabolism and the immune system, including neuroinflammation in the brain and spinal cord. Strikingly, there are also abnormalities of the peripheral immune system, with alterations of T lymphocytes, monocytes, complement and cytokines in the peripheral blood of patients with ALS. The precise contribution of the peripheral immune system in ALS pathogenesis is an active area of research. Although some trials of immunomodulatory agents have been negative, there is strong preclinical evidence of benefit from immune modulation and further trials are currently underway. Here, we review the emerging evidence implicating peripheral immune alterations contributing to ALS, and their potential as future therapeutic targets for clinical intervention.

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Monocytes of patients with amyotrophic lateral sclerosis linked to gene mutations display altered TDP‐43 subcellular distribution

Abstract: In ALS forms characterized by TDP-43 mislocalization in motor neurons, monocytes display this alteration, even when not manifest in CLM. Monocytes may be used to support diagnosis, as well as to identify subjects at risk, of ALS and to develop/monitor targeted treatments.

Cited by 26 publications

References 85 publications

ALS monocyte-derived microglia reveal cytoplasmic TDP-43 accumulation, DNA damage, and cell-specific impairment of phagocytosis associated with disease progression

ALS monocyte-derived microglia reveal cytoplasmic TDP-43 accumulation, DNA damage, and cell-specific impairment of phagocytosis associated with disease progression

The debated toxic role of aggregated TDP-43 in amyotrophic lateral sclerosis: a resolution in sight?

The Peripheral Immune System and Amyotrophic Lateral Sclerosis

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