Ubiquitin Specific Protease 13 Regulates Tau Accumulation and Clearance in Models of Alzheimer's Disease.

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.

• Authors: Xiaoguang Liu, Michaeline L Hebron, Sanjana Mulki, Chen Wang, Elizabeth Lekah, Dalila Ferrante, Wangke Shi, Bahjat Kurd-Misto, Charbel Moussa
• Journal: Journal of Alzheimer's disease : JAD (J Alzheimers Dis) Vol. 72 Issue 2 Pg. 425-441 ( 2019) ISSN: 1875-8908 [Electronic] Netherlands
• PMID: 31594232 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amyloid beta-Protein Precursor
• RNA, Small Interfering
• tau Proteins
• Endopeptidases
• USP13 protein, human
• Ubiquitin-Specific Proteases
• Proteasome Endopeptidase Complex

Topics

• Alzheimer Disease (metabolism, pathology)
• Amyloid beta-Protein Precursor (genetics)
• Animals
• Brain Chemistry (genetics)
• Cerebral Cortex (cytology, metabolism)
• Endopeptidases (genetics, metabolism)
• Gene Knockdown Techniques
• Humans
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Neurons (metabolism)
• Plaque, Amyloid (pathology)
• Proteasome Endopeptidase Complex
• RNA, Small Interfering
• Ubiquitin-Specific Proteases
• tau Proteins (metabolism)