Xie M, Liu YU, Zhao S, Zhang L, Bosco DB, Pang YP, Zhong J, Sheth U, Martens YA, Zhao N, Liu CC, Zhuang Y, Wang L, Dickson DW, Mattson MP, Bu G, Wu LJ. TREM2 interacts with TDP-43 and mediates microglial neuroprotection against TDP-43-related neurodegeneration. Nat Neurosci. 2022 Jan;25(1):26-38. Epub 2021 Dec 16 PubMed.

Recommends

Please login to recommend the paper.

Comments

  1. In this new study, Xie et al. report a novel role for TREM2 in microglial responses in an AAV-expressed, human TDP-43 model of amyotrophic lateral sclerosis (ALS), and they provide evidence of physical interactions between TREM2 and TDP-43. The authors propose that this interaction occurs during phagocytosis and show supporting biochemical evidence with various techniques. Overall, this interesting publication proposes a novel role for TREM2 and TREM2-mediated microglia activation in ALS pathology. Importantly, the physical interaction between TREM2 and TDP-43 potentially points to a new therapeutic application for anti-TREM2 antibodies currently being tested for Alzheimer’s disease.

    The study opens an exciting area of investigation that will be important to follow up and expand upon. Some notes of caution should be considered. It is important to note that whether TREM2 is a risk factor for ALS is still under debate (Lill et al., 2015; Cady et al., 2014). In the study that reported TREM2 as a risk factor, ALS was associated with the loss-of-function mutation R47H (Cady et al., 2014). However, neither the mass-spectra results, nor the molecular dynamics simulation in silico in this publication suggest the involvement of R47 residue in the interaction between TREM2 and TDP-43. Nevertheless, the surface plasmon resonance and co-immunoprecipitation data support the idea that TREM2 can bind to TDP-43 directly. Future studies to verify this interaction with crystal structure analysis will be important to resolve the discrepancy between binding and genetic risk.

    The authors also show that TDP-43 GFP+ puncta engulfed in the Iba1+ microglia co-localize with TREM2 puncta. This experiment provides suggestive in vivo evidence of physical interactions between TREM2 and TDP-43 that should be validated in the future with other independent approaches, as well as in other ALS models.

    References:

    Lill CM, Rengmark A, Pihlstrøm L, Fogh I, Shatunov A, Sleiman PM, Wang LS, Liu T, Lassen CF, Meissner E, Alexopoulos P, Calvo A, Chio A, Dizdar N, Faltraco F, Forsgren L, Kirchheiner J, Kurz A, Larsen JP, Liebsch M, Linder J, Morrison KE, Nissbrandt H, Otto M, Pahnke J, Partch A, Restagno G, Rujescu D, Schnack C, Shaw CE, Shaw PJ, Tumani H, Tysnes OB, Valladares O, Silani V, van den Berg LH, van Rheenen W, Veldink JH, Lindenberger U, Steinhagen-Thiessen E, SLAGEN Consortium, Teipel S, Perneczky R, Hakonarson H, Hampel H, von Arnim CA, Olsen JH, Van Deerlin VM, Al-Chalabi A, Toft M, Ritz B, Bertram L. The role of TREM2 R47H as a risk factor for Alzheimer's disease, frontotemporal lobar degeneration, amyotrophic lateral sclerosis, and Parkinson's disease. Alzheimers Dement. 2015 Dec;11(12):1407-1416. Epub 2015 Apr 30 PubMed.

    Cady J, Koval ED, Benitez BA, Zaidman C, Jockel-Balsarotti J, Allred P, Baloh RH, Ravits J, Simpson E, Appel SH, Pestronk A, Goate AM, Miller TM, Cruchaga C, Harms MB. TREM2 variant p.R47H as a risk factor for sporadic amyotrophic lateral sclerosis. JAMA Neurol. 2014 Apr;71(4):449-53. PubMed.

    View all comments by Marco Colonna

Make a Comment

To make a comment you must login or register.

This paper appears in the following:

News

  1. TREM2 Latches Onto TDP-43, Spurs Neuroprotective Microglial Mop-Up?