Scheiblich H, Dansokho C, Mercan D, Schmidt SV, Bousset L, Wischhof L, Eikens F, Odainic A, Spitzer J, Griep A, Schwartz S, Bano D, Latz E, Melki R, Heneka MT. Microglia jointly degrade fibrillar alpha-synuclein cargo by distribution through tunneling nanotubes. Cell. 2021 Sep 30;184(20):5089-5106.e21. Epub 2021 Sep 22 PubMed.

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  1. Love thy neighbor
    This is a truly fascinating study suggesting a new, and somewhat unexpected, set of cellular mechanisms that microglia might use to combat accumulation of pathogenic α-synuclein aggregates. Using a wide variety of complementary methods, the authors show that microglia might exchange α-synuclein fibrils with each other, at least in part via tunneling nanotubes, so that those microglia that are overburdened by the protein aggregates can share them with their less-stressed neighbors. In a similar vein, the less-compromised neighboring cells can send mitochondria over to the microglia that have taken up numerous α-synuclein fibrils. In a way, the cells are showing love for their neighbors.

    While researchers have thought for a long time that microglia might play an essential role in clearing α-synuclein aggregates, thereby possibly limiting the prion-like spread of aggregates between neurons, this study sheds new light on how this might take place.

    Very importantly, the most common monogenetic cause of Parkinson’s disease (G2019S LRRK2 mutation) was associated with impairments in the cellular communication between neighboring microglia. For some time, it has been suggested that LRRK2 mutations impact immune cell function and this study pinpoints one cell function that the mutations might affect.

    It would be interesting to know if other gene variants, e.g., related to GBA, also affect the processes described here. Furthermore, it will be interesting to learn more about the molecular mechanisms that control the exchange of protein aggregates and organelles between microglia, so that the traffic moves in the right direction.

    View all comments by Patrik Brundin

  2. This study may have important insights into how microglia deal with extracellular synuclein. While this may be triggered by initial cell death of cells with aggregated synuclein, it is likely to be an important piece of the jigsaw puzzle of how pathogenesis is perpetuated in synucleinopathies, and particularly how relatively few aggregates could lead to widespread changes in many microglial and astrocytic cells, a central step in CNS inflammation.

    One important question will be to examine how microglial degradation of the aggregates occurs within these cells. This is likely to be phagocytosis pathways that interact with lysosomes and possibly peroxidases. It will also be important to know how these degradative steps change with age, as microglia appear to become less competent, as well as potentially with LRRK2 mutations, as the authors have examined.

    It is also possible that these steps are involved in antigen presentation and lymphocyte activation in Parkinson’s. There is a lot to do on this topic, but this paper is providing a potentially very important insight on how synuclein aggregates are handled in the disease.

    View all comments by David Sulzer

  3. Parkinson’s disease is progressive, leading to worsening symptoms over time. This progression in symptoms has been correlated with the appearance of α-synuclein Lewy bodies in more regions through the brain over time. It has been hypothesized that misfolded α-synuclein may be released from neurons and internalized by nearby neurons, where it can propagate its pathological conformation through templated seeding. Studies in animal models have shown that this cell-to-cell transmission of pathological proteins can occur from neuron-to-neuron. The role that other resident brain cells, such as microglia, astrocytes, and oligodendrocytes, may play in this process is less clear. Microglia, with their phagocytic activity, should be poised to help neurons degrade extracellular proteins. However, recent studies have found that even microglia can get fatigued in this line of work, leading to inflammatory and deleterious phenotypes.

    In this remarkable new study, Scheiblich et al. examine what microglia do when challenged with misfolded α-synuclein. Similar to previous studies, Scheiblich and colleagues find that misfolded α-synuclein induces an inflammatory phenotype in cultured microglia that can eventually become toxic. However, microglia are not alone. The authors show that microglia can form a network with other microglia through tunneling nanotubes. When one microglia becomes overloaded with excess amounts of misfolded α-synuclein, it can offload this protein on its neighbor, effectively increasing its degradative capacity. Not only that, but the neighbor can also send some healthy mitochondria back to the overloaded microglia, reducing toxicity associated with handling misfolded proteins. The authors also show that microglia can transfer misfolded α-synuclein in vivo, although the extent of this analysis was limited.

    Several interesting questions arise from this study. How do microglia signal who needs help? Can neurons similarly signal to other neurons or microglia when their degradative capacity is compromised? In the event of neurodegeneration, can microglia form a bucket brigade of sorts that moves pathology out of a high-pathology area into less-burdened areas? Are microglia responsible for the spread of pathogenic proteins from one area to another?

    Recent studies have suggested that microglia, instead of protecting the brain, may aid in spreading α-synuclein across the brain (Guo et al., 2020; Xia et al., 2021). The authors of these studies suggested that microglia-derived exosomes, not direct contacts, are the responsible parties. Future studies will undoubtedly reveal more about the microglial network and how it interacts with the neural network in neurodegeneration.

    References:

    Guo M, Wang J, Zhao Y, Feng Y, Han S, Dong Q, Cui M, Tieu K. Microglial exosomes facilitate α-synuclein transmission in Parkinson's disease. Brain. 2020 May 1;143(5):1476-1497. PubMed.

    Xia Y, Zhang G, Kou L, Yin S, Han C, Hu J, Wan F, Sun Y, Wu J, Li Y, Huang J, Xiong N, Zhang Z, Wang T. Reactive microglia enhance the transmission of exosomal α-synuclein via toll-like receptor 2. Brain. 2021 Aug 17;144(7):2024-2037. PubMed.

    View all comments by Michael Henderson

  4. This is a very interesting paper that surely will stimulate discussions and further research in the field. The most convincing evidence for the suggested mechanism comes from in  vitro microglia cultures using prelabeled α-synthetic synuclein. The hypothesized mechanism is highly interesting, also in light of our recent findings that abundant microglial α-synuclein inclusions indeed develop in seeded brain slice cultures and endogenously in adult α-synuclein transgenic mice (Barth et al., 2021; Tanriöver et al., 2020).

    In our studies, microglial inclusions developed two to three  weeks later compared to neuronal inclusions and appeared biochemically and structurally different from neuronal α-synuclein inclusions. Because the appearance of the microglial inclusions was always linked to the neuronal inclusions both in magnitude and location, and because anti-α-synuclein antibody treatment blocked both neuronal and microglial inclusions, we hypothesized that the microglial inclusions contain αS of neuronal origins.

    Thus, it will be important to have a fresh look at the network dynamics and relationship between neuronal versus microglial α-synuclein inclusions with a focus on the suggested nanotube and cell-to-cell connections. The hypothesized and exciting cooperative strategy of pathogenic protein degradation of microglia will surely inspire the field to re-evaluate the contribution of microglia in disease progression when the degradation network fails.

    References:

    Barth M, Bacioglu M, Schwarz N, Novotny R, Brandes J, Welzer M, Mazzitelli S, Häsler LM, Schweighauser M, Wuttke TV, Kronenberg-Versteeg D, Fog K, Ambjørn M, Alik A, Melki R, Kahle PJ, Shimshek DR, Koch H, Jucker M, Tanriöver G. Microglial inclusions and neurofilament light chain release follow neuronal α-synuclein lesions in long-term brain slice cultures. Mol Neurodegener. 2021 Aug 11;16(1):54. PubMed.

    Tanriöver G, Bacioglu M, Schweighauser M, Mahler J, Wegenast-Braun BM, Skodras A, Obermüller U, Barth M, Kronenberg-Versteeg D, Nilsson KP, Shimshek DR, Kahle PJ, Eisele YS, Jucker M. Prominent microglial inclusions in transgenic mouse models of α-synucleinopathy that are distinct from neuronal lesions. Acta Neuropathol Commun. 2020 Aug 12;8(1):133. PubMed.

    View all comments by Gaye Tanriöver

  5. Decades of research have focused on neuronal abnormalities in Parkinson’s disease (PD), but recently more attention has been given to the glial cells. This elegant work by Michael Heneka and colleagues constitutes an important contribution to the field, highlighting the importance of microglia-to-microglia transfer in the clearance of pathological α-synuclein.

    To date, intercellular propagation of α-synuclein aggregates has mainly been considered a negative process, constituting a possible mechanism for spreading of PD pathology throughout the brain tissue. The data from Scheiblich et al. indicate that intercellular exchange of α-synuclein may instead limit the pathology and promote maintenance of a less-inflammatory microglia population.

    Interestingly, Scheiblich et al. describe that microglia promote trafficking of fibrillary α-synuclein, as well as mitochondria, via tunneling nanotubes (TNTs), in a fashion similar to that we have previously reported for astrocytes (Rostami et al., 2017). Moreover, the authors show that microglia carrying the LRRK2 G2019S mutation were unable to support neighboring cells in this fashion, and had difficulties sharing their burden of pathological α-synuclein. It would be interesting to investigate if aged microglia have similar limitations.

    Based on these findings, blocking cell-to-cell spreading of pathological proteins would not be an option for future therapeutic interventions. On the other hand, their study identifies cellular disease mechanisms, including mitochondria donation from healthy microglia to α-synuclein overloaded mitochondria, that may open up other treatment possibilities. 

    Uncovering the relevance of TNTs to the interplay between different cell types, including glial cells and neurons, would be important for better understanding the cellular cross-talk in the PD brain. Importantly, the authors used two-photon microscopy to demonstrate that α-synuclein aggregates also transfer between microglia in the living mouse brain, further supporting the importance of glial cells in PD pathology. A future challenge will be to elucidate whether the in vivo transfer is mainly mediated via TNTs or other cellular structures.

    References:

    Rostami J, Holmqvist S, Lindström V, Sigvardson J, Westermark GT, Ingelsson M, Bergström J, Roybon L, Erlandsson A. Human Astrocytes Transfer Aggregated Alpha-Synuclein via Tunneling Nanotubes. J Neurosci. 2017 Dec 6;37(49):11835-11853. Epub 2017 Oct 31 PubMed.

    View all comments by Anna Erlandsson

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