Graduation Year


Document Type




Degree Name

Doctor of Philosophy (Ph.D.)

Degree Granting Department

Medical Sciences

Major Professor

David E. Kang, Ph.D.

Committee Member

Yu Chen, Ph.D.

Committee Member

Kevin Nash, Ph.D.

Committee Member

Gopal Thinakaran, Ph.D.


autophagy, LC3, mitochondria, ubiquitin, tauopathy


Accumulation of toxic protein assemblies and damaged mitochondria are key features of neurodegenerative diseases, which arise in large part from clearance defects in the autophagy-lysosome system. The autophagy cargo receptor p62/SQSTM1 plays a major role in the clearance of ubiquitinated cargo through Ser403 phosphorylation by multiple kinases. However, no phosphatase is known to physiologically dephosphorylate p62 on this activating residue. RNAi-mediated knockdown and overexpression experiments using genetically encoded fluorescent reporters and defined mutant constructs in cell lines, primary neurons, and brains show that SSH1, the canonical cofilin phosphatase, mediates the dephosphorylation of phospho-Ser403-p62, thereby impairing p62 flux and phospho-tau clearance. The inhibitory action of SSH1 on p62 is fully dependent on p62 Ser403 phosphorylation status and is separable from SSH1-mediated cofilin activation. These findings reveal a bipartite action of SSH1 on p62 independent of cofilin and implicate an inhibitory role of SSH1 in p62-mediated clearance of autophagic cargo, including phospho-tau.

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Neurosciences Commons