Myeku N, Clelland CL, Emrani S, Kukushkin NV, Yu WH, Goldberg AL, Duff KE. Tau-driven 26S proteasome impairment and cognitive dysfunction can be prevented early in disease by activating cAMP-PKA signaling. Nat Med. 2016 Jan;22(1):46-53. Epub 2015 Dec 21 PubMed.
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University of Toronto
The paper by Myeku et al. describes elegant work and documents a critical role of the proteasome in the clearance of mutant tau. The authors are to be complimented for a careful analysis, which makes a compelling case that avenues to boost proteasomal activity might have merit for the treatment of tauopathies. Regarding the mechanism, the authors suggest that mutant tau may poison the proteasome by binding to it, but our recent work on tau protein-protein interactions shows that P301L tau binds more weakly to proteasomes than does wild-type tau (Gunawardana et al., 2015). These data suggest a modified interpretation, consistent with data presented in the new study. (Note that because tau knockout mice, rather than wild-type mice, served as negative controls in co-immunoprecipitations in the Myeku et al. paper, no conclusions about the relative binding propensity of tau versus mutant tau could be drawn.) Thus, we prefer a model whereby the interaction between mutant tau (P301L) and the proteasome is partially impaired relative to wild-type tau, perhaps contributing to poor proteasome processivity for this substrate. Over time, these altered properties of tau may lead to its aggregation and the appearance of proteotoxic effects on the proteasome. In either case, boosting proteasomal activity may compensate for the reduced rate of tau (P301L) clearance.
References:
Gunawardana CG, Mehrabian M, Wang X, Mueller I, Lubambo IB, Jonkman JE, Wang H, Schmitt-Ulms G. The Human Tau Interactome: Binding to the Ribonucleoproteome, and Impaired Binding of the Proline-to-Leucine Mutant at Position 301 (P301L) to Chaperones and the Proteasome. Mol Cell Proteomics. 2015 Nov;14(11):3000-14. Epub 2015 Aug 11 PubMed.
View all comments by Gerold Schmitt-UlmsUniversity of Edinburgh
This is an elegant study by Karen Duff's group examining proteasome dysfunction in rTg4510 mice. It is encouraging that enhancing proteasome activity appears to prevent or delay tau-associated pathology and cognitive decline in this model. Since treatment was no longer effective at later disease stages, this implies that for translational benefit, patients might need to be treated very early as is strongly indicated in anti-amyloid therapies. Based on our previous work implicating tau and ubiquitin proteasome system dysfunction in human synapses, it would be interesting to look for synapse recovery in the rolipram-treated mice.
View all comments by Tara Spires-JonesUniversity Maastricht
The ubiquitin-proteasome system #5—Time for a change
The present paper again reports a link between tau-driven 26S proteasome impairment and cognitive dysfunction, here prevented early in disease by activating cAMP-PKA signaling via Rolipram, a phosphodiester-4-inhibitor (PDE 4) developed for depression treatment (for details, see editors’ comments). This collaborative effort between Fred Goldberg and Karen Duff, pioneers in different fields, supports the view that the ubiquitin-proteasome system (UPS) is central in Alzheimer’s disease (AD). They used, as one of the many read-outs, a mouse tauopathy model for frontal temporal dementia with possible implications for AD, crossbred with a mouse reporter model of proteasome dysfunction developed and made available by Nico Dantuma’s group at Karolinska. In the absence of a better model for AD, currently this is the best strategy, while the promising three-dimensional culture system developed for AD by Rudi Tanzi’s group (Choi et al., 2014) may support the conclusions of the present paper. In addition, validation in fixed and frozen postmortem AD tissue may be possible, for instance of the phosphorylation of the Rpn6 proteasome lid subunit.
The present paper is in agreement with the view that the UPS is central in AD, as was already shown in a GWAS study (IGAP, 2015) and a proteomic study (Manavalan et al., 2013). Indeed, from previous evidence it turned out that the UPS is a relevant switch early in AD (e.g., Gentier and Van Leeuwen, 2015). Together, these findings point to proteasome activation via cAMP-PKA signaling, probably via Rpn6 subunit phosphorylation, “a potentially promising therapeutic approach to treatment of proteotoxic diseases,” as the authors write. Their suggestion is in line with recent work (see review of Heckman et al., 2015). In addition, UPS dysfunction resulting in loss of homeostasis may underlie propagation of this toxic tau form, and I suggest the authors include analysis of the brainstem in their mouse model studies. Why? It is now clear that the brainstem may be the area where AD is initiated (Irmler et al., 2012).
References:
Choi SH, Kim YH, Hebisch M, Sliwinski C, Lee S, D'Avanzo C, Chen H, Hooli B, Asselin C, Muffat J, Klee JB, Zhang C, Wainger BJ, Peitz M, Kovacs DM, Woolf CJ, Wagner SL, Tanzi RE, Kim DY. A three-dimensional human neural cell culture model of Alzheimer's disease. Nature. 2014 Nov 13;515(7526):274-8. Epub 2014 Oct 12 PubMed.
International Genomics of Alzheimer's Disease Consortium (IGAP). Convergent genetic and expression data implicate immunity in Alzheimer's disease. Alzheimers Dement. 2015 Jun;11(6):658-71. Epub 2014 Dec 20 PubMed.
Manavalan A, Mishra M, Feng L, Sze SK, Akatsu H, Heese K. Brain site-specific proteome changes in aging-related dementia. Exp Mol Med. 2013;45:e39. PubMed.
Gentier RJ, van Leeuwen FW. Misframed ubiquitin and impaired protein quality control: an early event in Alzheimer's disease. Front Mol Neurosci. 2015;8:47. Epub 2015 Sep 2 PubMed.
Heckman PR, Wouters C, Prickaerts J. Phosphodiesterase inhibitors as a target for cognition enhancement in aging and Alzheimer's disease: a translational overview. Curr Pharm Des. 2015;21(3):317-31. PubMed.
Irmler M, Gentier RJ, Dennissen FJ, Schulz H, Bolle I, Hölter SM, Kallnik M, Cheng JJ, Klingenspor M, Rozman J, Ehrhardt N, Hermes DJ, Gailus-Durner V, Fuchs H, Hrabě de Angelis M, Meyer HE, Hopkins DA, Van Leeuwen FW, Beckers J. Long-term proteasomal inhibition in transgenic mice by UBB(+1) expression results in dysfunction of central respiration control reminiscent of brainstem neuropathology in Alzheimer patients. Acta Neuropathol. 2012 Aug;124(2):187-97. PubMed.
View all comments by Fred van LeeuwenRIKEN Center for Brain Science
Good news for the holiday season. Knock-in substitution of the proteasome subunit phosphorylation site would further confirm the exclusive PKA-proteasome connection because PKA phosphorylates a number of proteins. At the later stage when proteasome activation fails to clear pathological tau, I suspect that autophagy might play some role. In any case, no one would have predicted that proteolysis, considered to be important only for digestion some decades ago, would be attracting so much attention now.
View all comments by Takaomi SaidoMake a Comment
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