Loss of mouse Stmn2 function causes motor neuropathy

Irune Guerra San Juan; Leslie A Nash; Kevin S Smith; Marcel F Leyton-Jaimes; Menglu Qian; Joseph R Klim; Francesco Limone; Alexander B Dorr; Alexander Couto; Greta Pintacuda; Brian J Joseph; D Eric Whisenant; Caroline Noble; Veronika Melnik; Deirdre Potter; Amie Holmes; Aaron Burberry; Matthijs Verhage; Kevin Eggan

doi:10.1016/j.neuron.2022.02.011

Loss of mouse Stmn2 function causes motor neuropathy

Neuron. 2022 May 18;110(10):1671-1688.e6. doi: 10.1016/j.neuron.2022.02.011. Epub 2022 Mar 15.

Authors

Irune Guerra San Juan¹, Leslie A Nash², Kevin S Smith², Marcel F Leyton-Jaimes², Menglu Qian², Joseph R Klim², Francesco Limone³, Alexander B Dorr², Alexander Couto², Greta Pintacuda⁴, Brian J Joseph², D Eric Whisenant⁵, Caroline Noble⁵, Veronika Melnik⁵, Deirdre Potter⁵, Amie Holmes⁵, Aaron Burberry⁶, Matthijs Verhage⁷, Kevin Eggan⁸

Affiliations

¹ Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA; Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, the Netherlands; Human Genetics, Amsterdam University Medical Center, 1081 HV Amsterdam, the Netherlands.
² Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
³ Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA; Leiden University Medical Center, 2333 ZA Leiden, the Netherlands.
⁴ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁵ Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
⁶ Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA; Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA.
⁷ Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, the Netherlands; Human Genetics, Amsterdam University Medical Center, 1081 HV Amsterdam, the Netherlands.
⁸ Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA. Electronic address: kevin.eggan@bmrn.com.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Amyotrophic Lateral Sclerosis* / genetics
Amyotrophic Lateral Sclerosis* / metabolism
Animals
Disease Models, Animal
Homozygote
Mice
Mice, Transgenic
Motor Neurons / metabolism
Neuromuscular Junction / metabolism
Stathmin* / genetics
Stathmin* / metabolism

Substances

Stathmin
Stmn2 protein, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding