Ubiquitin Specific Protease 13 Regulates Tau Accumulation and Clearance in Models of Alzheimer’s Disease¹

Article type: Research Article

Authors: Liu, Xiaoguang^{; *} | Hebron, Michaeline L. | Mulki, Sanjana | Wang, Chen | Lekah, Elizabeth | Ferrante, Dalila | Shi, Wangke | Kurd-Misto, Bahjat | Moussa, Charbel^{; *}

Affiliations: Translational Neurotherapeutics Program, Laboratory for Dementia and Parkinsonism, Department of Neurology, Georgetown University Medical Center, Washington, DC, USA

Correspondence: [*] Correspondence to: Charbel Moussa, MBBS, PhD, Associate Professor of Neurology, Director-Laboratory for Dementia and Parkinsonism, Scientific and Clinical Research Director- Translational Neurotherapeutics Program, Parkinson’s Foundation Center of Excellence, Director- Lewy Body Dementia Research Center of Excellence, Department of Neurology, Georgetown University Medical Center, 4000 Reservoir Rd, NW, Bldg D, Room 203C, Washington, DC 20057, USA. Tel.: +1 202 687 7328; E-mail: cem46@georgetown.edu and Xiaoguang Liu, MD/PhD, Assistant Professor of Neurology, Laboratory for Dementia and Parkinsonism, Translational Neurotherapeutics Program, Parkinson’s Foundation Center of Excellence, Lewy Body Dementia Research Center of Excellence, Department of Neurology, Georgetown University Medical Center, 4000 Reservoir Rd, NW, Bldg D, Room 267, Washington, DC 20057, USA. Tel.: +1 202 687 5146; E-mail: xl371@georgetown.edu.

Note: [1] This article received a correction notice (Erratum) post publication with DOI 10.3233/JAD-249007, available at http://doi.org/10.3233/JAD-249007.

Abstract: Ubiquitin Specific Protease-13 (USP13) is a de-ubiquinating enzyme that regulates protein ubiquitination and clearance. The role of USP13 is largely unknown in neurodegeneration. In this study we aim to demonstrate whether tau accumulation and/or clearance depends on ubiquitination/de-ubiquitination via USP-13. We used transgenic animal models of human amyloid precursor protein (APP) or P301L tau mutations and genetically knocked-down USP13 expression via shRNA to determine USP13 effects on tau ubiquitination and levels. We found a two-fold increase of USP13 levels in postmortem Alzheimer’s disease (AD) brains. USP13 knockdown significantly increased the activity of the 20S proteasome and reduced the levels of hyper-phosphorylated tau (p-tau) in primary cortical neurons. USP13 knockdown also reduced the levels of amyloid and increased p-tau ubiquitination and clearance in transgenic animal models that overexpress murine tau as a result of the expression of familial APP mutations (TgAPP) and the human mutant P301L tau (rTg4510), respectively. Clearance of p-tau appears to be mediated by autophagy in these animal models. Taken together, these data suggest that USP13 knockdown reduces p-tau accumulation via regulation of ubiquitination/de-ubiquitination and mediates its clearance via autophagy and/or the proteasome. These results suggest that USP13 inhibition may be a therapeutic strategy to reduce accumulation of plaques and toxic p-tau in AD and human tauopathies.

Keywords: Alzheimer’s disease, amyloid, tau, ubiquitin, USP13

DOI: 10.3233/JAD-190635

Journal: Journal of Alzheimer's Disease, vol. 72, no. 2, pp. 425-441, 2019