4.6 Article

UCH-L1 Inhibition Suppresses tau Aggresome Formation during Proteasomal Impairment

Journal

MOLECULAR NEUROBIOLOGY
Volume 55, Issue 5, Pages 3812-3821

Publisher

HUMANA PRESS INC
DOI: 10.1007/s12035-017-0558-7

Keywords

Ubiquitin carboxy-terminal hydrolase L1; Tau aggresome; K63-linkedubiquitinchains; Histone deacetylase 6

Categories

Funding

  1. Nature Science foundation of Hubei Province [2016CFB561]
  2. project of Hubei Key Laboratory of Genetic Regulation and Integrative Biology [GRIB201604]
  3. National Natural Science Foundation of China [31372212]

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In conditions of proteasomal impairment, the damaged or misfolded proteins, collectively known as aggresome, can accumulate in the perinuclear space and be subsequently eliminated by autophagy. Abnormal aggregation of microtubule-associated protein tau in the cytoplasm is a common neuropathological feature of tauopathies. The deficiency in ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), a proteasomal deubiquitinating enzyme, is closely related to tau aggregation; however, the associated mechanisms remain unclear. Here, we showed that UCH-L1 inhibition interrupts proteasomal impairment-induced tau aggresome formation. By reducing the production of lysine (K63)-linked ubiquitin chains, UCH-L1 inhibition decreases HDAC6 deacetylase activity and attenuates the interaction of HDAC6 and tau protein, finally leading to tau aggresome formation impairment. All these results indicated that UCH-L1 plays a key role in the process of tau aggresome formation by regulating HDAC6 deacetylase activity and implied that UCH-L1 may act as a signaling molecule to coordinate the effects of the ubiquitin-proteasome system and the autophagy-lysosome pathway, which mediate protein aggregates degradation in the cytoplasm.

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