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Zhang Z, Song M, Liu X, Kang SS, Kwon IS, Duong DM, Seyfried NT, Hu WT, Liu Z, Wang JZ, Cheng L, Sun YE, Yu SP, Levey AI, Ye K. Cleavage of tau by asparagine endopeptidase mediates the neurofibrillary pathology in Alzheimer's disease. Nat Med. 2014 Nov;20(11):1254-62. Epub 2014 Oct 19 PubMed.
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This is a very comprehensive study where the authors have used various techniques and models to show that a specific endopeptidase (AEP) degrades tau. It has been known for some years that tau is degraded and fragments of tau have previously been detected in both human brain tissue and cerebrospinal fluid (CSF) (see, for example, Zilka et al., 2012; Meredith et al., 2013). However, the exact molecular nature of the tau fragments has so far been difficult to determine. In the study by Zhang and colleagues, they show the exact cleavage sites for AEP. From a biomarker perspective, it would have been interesting to know if these AEP-generated fragments are present in CSF and if so, how would these tau fragments perform in an Alzheimer's disease and control study.
University of Kiel
University Kiel
The study unequivocally shows a predominent role of asparagine endopeptidase (AEP)/legumain in the degradation of tau, and precisely determines the cleavage site of the asparagine-specific protease. The absence of AEP-derived tau fragments in AEP-knockout mice proves the in vitro data. However, a central question related to the topology of molecular events mediated by this protease in the paper from Zhang et al. remains unanswered: If AEP is a lysosomal protease, how does tau fragmentation occur mainly in the cytosol?
The authors speculate that AEP is translocated to the cytosol under specific conditions, where it might act on tau. However, they also present clear data that AEP is inactive at cytosolic pH and is only able to cleave tau under acidic conditions. Previous studies had shown, moreover, that AEP is irreversibly inactivated and denatured under neutral pH conditions (Chen et al., 1997). Taken together, cytosolic tau degradation by AEP seems unlikely.
Tau was previously shown to be degraded at least in part by autophagy, with both chaperone-mediated autophagy and macroautophagy playing a role (for detailed reviews see Wang et al., 2010; Wang and Mandelkow 2012). Very recently, phosphatidylinositol-binding clathrin assembly protein (PICALM) was shown to modulate autophagy and thereby tau accumulation (Moreau et al., 2014). Finally, overexpression of the transcription factor EB (TFEB) was recently shown to mediate the clearance of toxic tau species in the rTg4510 mouse model of tauopathy (Polito et al., 2014).
It remains to be clarified if AEP proteolysis of tau occurs in the cytosol or in autolysosomes after autophagic engulfment. This question has a major impact on possible therapeutic interventions aimed at AEP as a target.
References:
Chen JM, Dando PM, Rawlings ND, Brown MA, Young NE, Stevens RA, Hewitt E, Watts C, Barrett AJ. Cloning, isolation, and characterization of mammalian legumain, an asparaginyl endopeptidase. J Biol Chem. 1997 Mar 21;272(12):8090-8. PubMed.
Wang Y, Martinez-Vicente M, Krüger U, Kaushik S, Wong E, Mandelkow EM, Cuervo AM, Mandelkow E. Synergy and antagonism of macroautophagy and chaperone-mediated autophagy in a cell model of pathological tau aggregation. Autophagy. 2010 Jan;6(1):182-3. PubMed.
Wang Y, Mandelkow E. Degradation of tau protein by autophagy and proteasomal pathways. Biochem Soc Trans. 2012 Aug;40(4):644-52. PubMed.
Moreau K, Fleming A, Imarisio S, Lopez Ramirez A, Mercer JL, Jimenez-Sanchez M, Bento CF, Puri C, Zavodszky E, Siddiqi F, Lavau CP, Betton M, O'Kane CJ, Wechsler DS, Rubinsztein DC. PICALM modulates autophagy activity and tau accumulation. Nat Commun. 2014 Sep 22;5:4998. PubMed.
Polito VA, Li H, Martini-Stoica H, Wang B, Yang L, Xu Y, Swartzlander DB, Palmieri M, di Ronza A, Lee VM, Sardiello M, Ballabio A, Zheng H. Selective clearance of aberrant tau proteins and rescue of neurotoxicity by transcription factor EB. EMBO Mol Med. 2014 Jul 28;6(9):1142-60. PubMed.
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