Clinging on: Tau & the Proteasome
Reviewed by: Luca Nart, Clare College, Cambridge, UK. No conflicts of interest declared.
Tauopathies are a diverse set of neurodegenerative disorders associated with the aggregation of a modified native protein – Tau – in nerve tissue. Uncovering why, where and when Tau misbehaves is one of the cornerstones of Alzheimer’s research and has been a focus of funding since the central role of Tau was discovered in the late 1980s. Recent work by Myeku et al. reveals Tau’s direct inhibition of a cellular refuse system, the proteasome, allowing further Tau aggregation and neuron loss in murine models. Excitingly, Myeku et al. also reveal how this inhibition can be relieved and cognitive decline reversed in vivo with use of a drug widely used in research, Rolipram.
The 26S proteasome is the destination for cellular proteins that have reached the end of their lifespan, degrading peptides for reuse or metabolism. Myeku et al. used transgenic rTg4510 mice expressing a mutant tau– an animal model commonly used in tauopathy research. Primary tauopathies and tau-associated conditions such as AD commonly present as insoluble plaques of oligomeric Tau and it is these that are associated with neuronal dysfunction and eventual death. An aspect of this accumulation is reduced breakdown of Tau. Previous work by Dickey et al. has confirmed the upstream effects of Tau in turning off the chaperone system that guides the protein, but the direct effects of Tau on the proteasome had remained obscure until this recent publication.
The study begins by confirming the role of reduced Tau degradation in a murine model expressing pathogenic P301L tau. They noted reduced peptidase activity and increased ubiquinated protein (the cellular tag for proteins destined for the proteasome), later confirmed in vitro with the use of ubiquinated GFP. These isolates were later shown to be physically associated with Tau, rather than interference with an upstream process. This reveals Tau’s role as a proteotoxin, driving further aggregation and further proteasome inhibition. This association was further found to be restricted to pathogenic, insoluble tau rather than healthy wild-type Tau. Such a positive feedback mechanism seems to key of tauopathy pathogenesis.
Myeku et al. extended these investigations to the role of the cAMP-PKA pathway – a crucial signaling mechanism in cells with wide-ranging effects. Increasing the activity of this system through using the phosphodiesterase (PDE4) inhibitor Rolipram restored proteasome activity both in vivo and in vitro. rTg4510 mice inoculated with Rolipram saw improved cognitive performance and spatial reference compared with control counterparts. These effects were observed when Rolipram was provided both prophylactically and at early-moderate stages of disease progression, but not at later stages of their conditions. Myeku et al. later hypothesised that phosphorylation of PKA prevented possible binding of Tau to the ATPase domain of the proteasome (that provides energy for the process), similar to PrPsc seen in scrapie.
Perhaps most compelling is that these cognitive benefits are provided by Rolipram, a PDE4 inhibitor initially developed by as an antidepressant in the 1990s. In spite of Rolipram being discontinued in clinical trials due to a narrow therapeutic window, the significant gastrointestinal side effects appear to have been surmounted in other PDE inhibitors licensed for use in the US, including Roflumistat for COPD. Pfizer and Merck have both entered PDE4 inhibitors into Phase II clinical trials for use in AD but results have yet to be published.
Moreover, the reversal (rather than delayed onset) of behavioral changes seen in this mouse model demonstrates an important clinical implication. Our current lack of biomarkers for cognitive impairment leaves us unable to accurately anticipate these changes in AD patients and as such treatment is often restricted to when patient cognition has already declined. A drug that has efficacy even after onset of impairment would have important applications. However, the underlying pathology of Alzheimer’s still remains unclear – unlike a primary tauopathy the role of tau in AD aetiology is unclear and other major factors such as Amyloid-b aggregation are at play. It remains to be seen whether this animal model and Rolipram’s effects are applicable to human AD pathogenesis.
The attraction of a small molecular drug that is affordable, with analogues in current clinical use and which can be repurposed for its neuroprotective effects is undeniable. This enthusiasm must of course be tempered by the lack of data regarding reproducibility in patients, the effects of other PDE4 inhibitors and safety concerns, but there is room for optimism yet.
Myeku, N., Clelland, C. L., Emrani, S., Kukushkin, N. V, Yu, W. H., Goldberg, A. L., & Duff, K. E. (2016). Tau-driven 26S proteasome impairment and cognitive dysfunction can be prevented early in disease by activating cAMP-PKA signaling. Nat Med, 22(1), 46–53. Retrieved from http://dx.doi.org/10.1038/nm.4011
ACNR 2016;15(6). Online first 22/1/2016