@article{37369e07d81a407cb1b138351f80d929,
title = "Loss of mouse Stmn2 function causes motor neuropathy",
abstract = "Amyotrophic lateral sclerosis (ALS) is characterized by motor neuron degeneration accompanied by aberrant accumulation and loss of function of the RNA-binding protein TDP43. Thus far, it remains unresolved to what extent TDP43 loss of function directly contributes to motor system dysfunction. Here, we employed gene editing to find whether the mouse ortholog of the TDP43-regulated gene STMN2 has an important function in maintaining the motor system. Both mosaic founders and homozygous loss-of-function Stmn2 mice exhibited neuromuscular junction denervation and fragmentation, resulting in muscle atrophy and impaired motor behavior, accompanied by an imbalance in neuronal microtubule dynamics in the spinal cord. The introduction of human STMN2 through BAC transgenesis was sufficient to rescue the motor phenotypes observed in Stmn2 mutant mice. Collectively, our results demonstrate that disrupting the ortholog of a single TDP43-regulated RNA is sufficient to cause substantial motor dysfunction, indicating that disruption of TDP43 function is likely a contributor to ALS.",
keywords = "ALS, CRISPR, SCG10, TARDBP, TDP43, microtubules, motor neuron, motor neuropathy, neuromuscular junction, stathmin 2",
author = "{Guerra San Juan}, Irune and Nash, {Leslie A.} and Smith, {Kevin S.} and Leyton-Jaimes, {Marcel F.} and Menglu Qian and Klim, {Joseph R.} and Francesco Limone and Dorr, {Alexander B.} and Alexander Couto and Greta Pintacuda and Joseph, {Brian J.} and Whisenant, {D. Eric} and Caroline Noble and Veronika Melnik and Deirdre Potter and Amie Holmes and Aaron Burberry and Matthijs Verhage and Kevin Eggan",
note = "Funding Information: Support to K.E. was provided by Target ALS , NIH 5R01NS089742 , Bristol Myers Squibb, and the Harvard Stem Cell Institute . I.G.S.J. is supported by Target ALS . L.A.N. is the recipient of the Healey Scholars Fellowship. A.B. was supported by NIH 5K99AG057808-02 . J.R.K. was supported by the Tom Kirchhoff Family Postdoctoral Fellowship from Project ALS . Funding Information: Support to K.E. was provided by Target ALS, NIH 5R01NS089742, Bristol Myers Squibb, and the Harvard Stem Cell Institute. I.G.S.J. is supported by Target ALS. L.A.N. is the recipient of the Healey Scholars Fellowship. A.B. was supported by NIH 5K99AG057808-02. J.R.K. was supported by the Tom Kirchhoff Family Postdoctoral Fellowship from Project ALS. We thank Joanie Mok for sharing her insight and expertise on animal handling. We thank the Harvard Center for Biological Imaging, the Harvard Genome Modification Facility, and the HSCRB Histology Core for infrastructure and support. Schematic diagrams in all Figures were generated with BioRender.com. Conceptualization, K.E.; methodology, I.G.S.J. L.A.N. K.S.S. M.F.L.-J. M.Q. A.B. J.R.K. F.L. A.B.D. A.C. G.P. B.J.J. D.E.W. C.N. V.M. D.P. A.H. and K.E.; validation, L.A.N. I.G.S.J. M.F.L.-J. and A.B.D.; formal analysis, I.G.S.J. L.A.N. K.S.S. and M.F.L.-J.; investigation, I.G.S.J. L.A.N. K.S.S. M.F.L.-J. M.Q. A.B. J.R.K. F.L. A.B.D. A.C. G.P. B.J.J. D.E.W. C.N. V.M. D.P. and A.H.; resources, K.E.; writing – original draft, I.G.S.J. L.A.N. and K.E.; writing – review & editing, I.G.S.J. L.A.N. A.B. J.R.K. F.L. M.F.L.-J. K.S.S. B.J.J. M.V. and K.E.; visualization; I.G.S.J. L.A.N. J.R.K. F.L. A.B. M.V. and K.E.; supervision, I.G.S.J. L.A.N. M.V. and K.E.; project administration, K.E.; and funding acquisition, K.E. K.E. is a cofounder of Q-State Biosciences, Quralis, and Enclear Therapies and currently head of research and early development at BioMarin Pharmaceutical. J.R.K. is an employee of Faze Medicines and a shareholder in Faze Medicines and QurAlis. K.E. I.G.S.J. J.R.K. and F.L. are authors on a pending patent that describes methods and compositions for restoring STMN2 levels (WO/2020/150290). K.E. is an author on a pending patent that describes compounds and methods for treating neurodegenerative diseases (WO2020107037). We worked to ensure sex balance in the selection of non-human subjects. One or more of the authors of this paper self-identifies as a member of the LGBTQ+ community. One or more of the authors of this paper self-identifies as living with a disability. While citing references scientifically relevant for this work, we also actively worked to promote gender balance in our reference list. Publisher Copyright: {\textcopyright} 2022 Elsevier Inc.",
year = "2022",
month = may,
day = "18",
doi = "https://doi.org/10.1016/j.neuron.2022.02.011",
language = "English",
volume = "110",
pages = "1671--1688.e6",
journal = "Neuron",
issn = "0896-6273",
publisher = "Cell Press",
number = "10",
}