While appreciating the impressive FALS study by Sexena et al., I could not help frowning on the comment by P.F. Jennings: Why implicate protein tau and axonal transport? Tau-4R transgenic mice develop axonopathy leading to Wallerian degeneration and muscle wasting, but not premature death (Spittaels et al., 1999), as opposed to tau-P301L mice that develop tauopathy and die prematurely (Terwel et al., 2005).
Both patho-phenotypes are affected by co-expression of GSK3, albeit quite differently: rescue and aggravation of tauopathy, respectively (Spittaels et al., 2000; Terwel et al., 2008).
Our simplest explanation: excess tau-4R (but not tau-P301L) occupies microtubular binding sites, preventing motor proteins to walk and transport "stuff." GSK3 phosphorylates tau and releases it from the MT to allow transport again, but thereby causes tauopathy at the expense of axonopathy. Why motor neurons are most sensitive to tau-induced degeneration remains an open question. Caroni and co-workers provide possible indications.
But is protein tau involved in ALS?
Spittaels K, Van den Haute C, Van Dorpe J, Bruynseels K, Vandezande K, Laenen I, Geerts H, Mercken M, Sciot R, Van Lommel A, Loos R, Van Leuven F. Prominent axonopathy in the brain and spinal cord of transgenic mice overexpressing four-repeat human tau protein. Am J Pathol. 1999 Dec;155(6):2153-65. Abstract
Spittaels K, Van den Haute C, Van Dorpe J, Geerts H, Mercken M, Bruynseels K, Lasrado R, Vandezande K, Laenen I, Boon T, Van Lint J, Vandenheede J, Moechars D, Loos R, Van Leuven F. Glycogen synthase kinase-3beta phosphorylates protein tau and rescues the axonopathy in the central nervous system of human four-repeat tau transgenic mice. J Biol Chem. 2000 Dec 29;275(52):41340-9. Abstract
Terwel D, Lasrado R, Snauwaert J, Vandeweert E, Van Haesendonck C, Borghgraef P, Van Leuven F. Changed conformation of mutant Tau-P301L underlies the moribund tauopathy, absent in progressive, nonlethal axonopathy of Tau-4R/2N transgenic mice. J Biol Chem. 2005 Feb 4;280(5):3963-73. Abstract
Terwel D, Muyllaert D, Dewachter I, Borghgraef P, Croes S, Devijver H, Van Leuven F. Amyloid activates GSK-3beta to aggravate neuronal tauopathy in bigenic mice. Am J Pathol. 2008 Mar;172(3):786-98. Abstract
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