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Rao MV, McBrayer MK, Campbell J, Kumar A, Hashim A, Sershen H, Stavrides PH, Ohno M, Hutton M, Nixon RA. Specific calpain inhibition by calpastatin prevents tauopathy and neurodegeneration and restores normal lifespan in tau P301L mice. J Neurosci. 2014 Jul 9;34(28):9222-34. PubMed.
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Deceased
This is a nice paper, and perhaps the only issue I see is that the authors choose to use a very mild pathology model, the heterozygous P301L mouse. The effects of calpain inhibition were significant in this model, but I would argue that to compare the effectiveness of inhibition with that reported by other groups who used the homozygous model (more common) is pushing matters a little.
As regards therapy, one wonders how a lifetime of expression of an anti-tau antibody would do compared to lifelong expression of calpastatin.
University of West Florida
The work by Rao and colleagues highlights the importance of proteolytic dynamics in neurodegeneration, placing the calcium-dependent protease, calpain, in the center of the universe. Evidence for calpain involvement in neurodegeneration has grown in the last 20 years as further demonstrated in this P301L tauopathy model. This timely research builds a strong case for deeper investigation of how tau proteolysis contributes to the neurodegenerative process, including as it relates to AD. While other proteases are involved in tau processing, calpains indeed play a central role and the present work provides support for selective targeting of calpains to attenuate tau-centric neurodegeneration. One hurdle to overcome in the development of a calpain strategy will be to allow normal calpain activity to take place. Like virtually all enzymes linked to disease, calpain has a physiological role to play and potent inhibition has potentially negative consequences. One of the beauties of the calpain protease is that the highly active form detected in this study is more closely associated with pathology. Therefore, targeting this form may provide a unique opportunity to decrease the pathological actions while maintaining the physiological function. As noted by Rao et al., targeting calpains has been a challenge, but I believe it can be overcome.
Lille Neuroscience & Cognition
This is a nice article. One could ask why calpastatin is downregulated. Since proteasome inhibition may modulate calpain activity, what is the status of the proteasome in JNLP3 mice?
References:
Delobel P, Leroy O, Hamdane M, Sambo AV, Delacourte A, Buée L. Proteasome inhibition and Tau proteolysis: an unexpected regulation. FEBS Lett. 2005 Jan 3;579(1):1-5. PubMed.
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