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Upper motor neurons are a target for gene therapy and UCHL1 is necessary and sufficient to improve cellular integrity of diseased upper motor neurons

Gene Therapy volume 29, pages 178–192 (2022)Cite this article

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A Comment to this article was published on 20 January 2022

Abstract

There are no effective cures for upper motor neuron (UMN) diseases, such as amyotrophic lateral sclerosis (ALS), primary lateral sclerosis, and hereditary spastic paraplegia. Here, we show UMN loss occurs independent of spinal motor neuron degeneration and that UMNs are indeed effective cellular targets for gene therapy, which offers a potential solution especially for UMN disease patients. UCHL1 (ubiquitin C-terminal hydrolase-L1) is a deubiquitinating enzyme crucial for maintaining free ubiquitin levels. Corticospinal motor neurons (CSMN, a.k.a UMNs in mice) show early, selective, and profound degeneration in Uchl1nm3419 (UCHL1−/−) mice, which lack all UCHL1 function. When UCHL1 activity is ablated only from spinal motor neurons, CSMN remained intact. However, restoring UCHL1 specifically in CSMN of UCHL1−/− mice via directed gene delivery was sufficient to improve CSMN integrity to the healthy control levels. In addition, when UCHL1 gene was delivered selectively to CSMN that are diseased due to misfolded SOD1 toxicity and TDP-43 pathology via AAV-mediated retrograde transduction, the disease causing misfolded SOD1 and mutant human TDP-43 were reduced in hSOD1G93A and prpTDP-43A315T models, respectively. Diseased CSMN retained their neuronal integrity and cytoarchitectural stability in two different mouse models that represent two distinct causes of neurodegeneration in ALS.

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Fig. 1: UCHL1 expression can be deleted using cre/lox conditional mutant approach in the CSMN of floxed UCHL1 mice.
Fig. 2: HB9cre UCHL1f/f mice lack UCHL1 in their spinal motor neurons.
Fig. 3: Cortex specific UCHL1 conditional mutant mice recapitulate pathology observed in the CSMN of UCHL1−/− mice.
Fig. 4: Spine density is reduced in degenerating and vacuolated apical dendrites of CSMN.
Fig. 5: UCHL1 expression can be restored in CSMN of UCHL1−/− mice using a AAV2-UCHL1-IRES-eGFP bicistronic expression vector.
Fig. 6: Restoration of UCHL1 expression in only CSMN of UCHL1−/− mice is sufficient to improve their health and cytoarchitectural integrity.
Fig. 7: Expression of UCHL1 in CSMN of hSOD1G93A mice is sufficient to improve their health and cytoarchitectural integrity.
Fig. 8: Expression of UCHL1 in CSMN of prpTDP-43A315T mice is sufficient to improve their health and cytoarchitectural integrity.
Fig. 9: UCHL1 expression reduces both the levels of misfolded SOD1 and human TDP-43A315T.

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Acknowledgements

We thank UPenn Viral Vector Core, Bill Goosens, and Jolanta Topczewska microscopy at the Stanley Manne Research Institute Lurie Children’s Microscopy and Imaging Facility for help with the confocal microscope.

Funding

This work was supported by grants from NIH-R01NS085161-01 (to P.H.O.), NUCATS (to P.H.O.), and in part by Mitsubishi Tanabe Pharma Holdings America, Inc. (to P.H.O.). The Northwestern University Transgenic and Targeted Mutagenesis Laboratory are partially supported by NIH grant CA60553 to the Robert H. Lurie Comprehensive Cancer Center at Northwestern University.

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  1. These authors contributed equally: Barış Genç, Javier H. Jara.

Authors and Affiliations

  1. Davee Department of Neurology and Clinical Neurological Sciences, Northwestern University, Feinberg School of Medicine, Chicago, IL, 60611, USA

    Barış Genç, Javier H. Jara, Santana S. Sanchez, Amiko K. B. Lagrimas, Öge Gözütok, Nuran Koçak & P. Hande Özdinler

  2. Departments of Ophthalmology and Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA

    Yongling Zhu

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  1. Barış Genç
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Contributions

J.H.J., B.G., S.S.S., A.K.B.L., O.G., N.K., and P.H.O. performed experiments. J.H.J., B.G., S.S.S., and P.H.O. analyzed data, and J.H.J., B.G., and P.H.O. contributed to the writing of this manuscript.

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Correspondence to P. Hande Özdinler.

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Genç, B., Jara, J.H., Sanchez, S.S. et al. Upper motor neurons are a target for gene therapy and UCHL1 is necessary and sufficient to improve cellular integrity of diseased upper motor neurons. Gene Ther 29, 178–192 (2022). https://doi.org/10.1038/s41434-021-00303-4

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  • DOI: https://doi.org/10.1038/s41434-021-00303-4

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