Spiller KJ, Restrepo CR, Khan T, Dominique MA, Fang TC, Canter RG, Roberts CJ, Miller KR, Ransohoff RM, Trojanowski JQ, Lee VM. Microglia-mediated recovery from ALS-relevant motor neuron degeneration in a mouse model of TDP-43 proteinopathy. Nat Neurosci. 2018 Mar;21(3):329-340. Epub 2018 Feb 20 PubMed.

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  1. This paper from Virginia Lee's group features further characterization of mice with doxycycline-suppressible expression of human TDP-43, including a defective nuclear localization signal (Walker et al., 2015). Importantly, the expression of the human TDP-43 is almost entirely limited to neuronal cells by placing it under control of a neurofilament heavy chain promoter. The groundbreaking aspect of this model is that while the mice develop TDP-43 pathology and neuronal toxicity when the human gene is expressed, when expression is turned off the pathology is cleared and motor neuron loss ceases.

    In this paper Spiller et al. describe analysis of the role of microglia in this process. The authors did not observe significant microgliosis during the period in which the mice were losing motor neurons, but in the recovery phase there was an increase in reactive microglia which were observed to clear human TDP-43 through contact with diseased neurons. This effect was not a byproduct of doxycycline, and was necessary for motor recovery—when microglia were suppressed recovery did not occur.

    The immediate inference of this work is that microglia are necessary for recovery of motor neurons in human patients with ALS where TDP-43 pathology is almost universal. The authors suggest that modulation of microglial activity may be an attractive therapeutic target; indeed, certain microglial phenotypes have previously been linked to clinical severity in ALS patients (e.g., Cooper-Knock et al., 2017). Some caution should be reserved, however, because aspects of the model are not obviously physiological: The authors point out that it is unclear why significant microglial activation did not occur in the period when the human gene was being actively expressed. The microglia themselves do not express the human gene, so a direct effect of defective TDP-43 protein is not a possible answer. What is clear is that the change in microglial activity is entirely dependent on the change in expression of the human gene; this event has no parallel in the human disease. Understanding the basis of this observation is crucial to understanding this model and I suspect will offer further insights into human ALS as well.

    References:

    Walker AK, Spiller KJ, Ge G, Zheng A, Xu Y, Zhou M, Tripathy K, Kwong LK, Trojanowski JQ, Lee VM. Functional recovery in new mouse models of ALS/FTLD after clearance of pathological cytoplasmic TDP-43. Acta Neuropathol. 2015 Nov;130(5):643-60. Epub 2015 Jul 22 PubMed.

    Cooper-Knock J, Green C, Altschuler G, Wei W, Bury JJ, Heath PR, Wyles M, Gelsthorpe C, Highley JR, Lorente-Pons A, Beck T, Doyle K, Otero K, Traynor B, Kirby J, Shaw PJ, Hide W. A data-driven approach links microglia to pathology and prognosis in amyotrophic lateral sclerosis. Acta Neuropathol Commun. 2017 Mar 16;5(1):23. PubMed.

    View all comments by Johnathan Cooper-Knock

  2. Disease-associated microglia (DAM) emerged last year as a shared hallmark of brain aging, AD-like pathology in 5xFAD and PS2APP and APPPS1 models, ALS in mSOD1 model, and other neurodegenerative conditions (Keren-Shaul et al., 2017; Krasemann et al., 2017). The transcriptional profile of DAM cells, compared to that of homeostatic microglia, involves changes in expression of genes identified as risk factors in neurodegeneration (Lambert et al., 2013), suggesting that DAM are protective cells that clear apoptotic bodies, myelin debris, and Aβ, and create a barrier around bigger amyloid plaques to limit their toxicity (Krasemann et al., 2017; Poliani et al., 2015; Song et al., 2017; Song et al., 2018; Yuan et al., 2016). 

    Mislocalization and aggregation of TDP-43 is a common feature of FTD and ALS. Using a doxocyclin-controlled human TDP-43–mediated ALS model, Spiller et al. illuminate the role of microglia in TDP-43 pathology. They find that TDP-43 acts as a negative regulator of microglial differentiation into cells displaying markers of DAM (e.g., expression of Apoe, Itgax, Spp1, Lpl, Ctsb and Ctsd). A very important finding was reported here: In the late disease and early recovery phase (after hTDP-43 expression was suppressed), microglia differentiated dramatically to DAM (Supplementary Fig. 10) and cleared neuronal TDP-43 (Fig. 7). Blocking microglia in the early recovery phase using PLX3397 suppressed the ability to recover motor function (Fig.8), demonstrating the protective role of activated microglia in this context.

    Besides this great scientific advancement in our understanding of the role of TDP-43 and microglia in ALS pathology, this paper should set the direction for the future work in the field in several ways:

    1. We should use mouse models that more accurately reflect human conditions. Here the authors used a model of human TDP-43 pathology, which is present in >90 percent of ALS patients. In contrast, the most popular model of ALS, the mSOD1 mice, corresponds to only 3 percent of human ALS cases associated with SOD1 mutation.
    2. We should incorporate more molecular data from human samples to our mouse-based research. Spiller et al. find confirmation of their initial findings from mouse models in human spinal cord specimens of patients with different mutations corresponding to animal models used in the mouse study.
    3. The combination of advanced genetic and molecular tools needs to be incorporated to elucidate the cross-talk and dynamics of the pathology.
    4. We need to better understand the mechanism of how TDP-43 suppresses microglial ability to differentiate into DAM.
    5. We need to test if suppression of DAM activity is a common mechanism in other neurodegeneration conditions, and what are the suppressive factors.

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    View all comments by Aleksandra Deczkowska

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