Despite progress along several fronts, many crucial questions around tau remain unanswered. Some may appear literally of academic interest, but their elucidation will inform diagnostic and therapeutic approaches to tauopathies. From molecule to organism, here is a partial list that does not include equally important questions connected to tau post-translational modifications (de/phosphorylation, nitration, glycosylation, truncation) or degradation pathways:
Which model of the splicing regulation at the 5′ splice site of exon 10 is correct? The two theories (stem-loop versus linear) are not mutually exclusive but resolution is important as an aid to designs of future RNA-based interventions, even after we have solved the thorny issues of how to deliver and calibrate the expression of such constructs.
How does the imbalance of tau isoforms cause neurodegeneration? Since neurodegeneration occurs regardless of which way the ratio of exon 10 tilts, the inevitable conclusion is that balance between 3R and 4R isoforms must remain within a narrow window to ensure normal neuronal function. This correlates with the finding that mice which overexpress tau develop severe neuropathies or gliopathies regardless of transgene details (Brandt et al., 2005
; LaFerla, 2010
Perhaps the 1:1 3R:4R ratio is critical for correct MT dynamics in specific contexts within the various cell types of the human brain, a balancing act between fluidity and stability. Alternatively or additionally, ratio imbalances of the domains encoded by alternatively spliced exons can influence tau subcellular localization and interactions with other cytoskeletal or membrane components, including regulatory kinases and phosphatases (Gendron and Petrucelli, 2009
Which is the neurotoxic tau species? Results from animal, cellular and in vitro models give inconsistent results: some support the long-held view that tau aggregated in NFTs is the culprit, while others indicate that NFTs are inert, safe “warehouses” of otherwise toxic soluble tau species (Götz et al., 2008
; Sahara et al., 2008
; Jellinger, 2009
). The latter theory gains support from both invertebrate and vertebrate animal models that overexpress tau, in which neurodegeneration and cognitive impairment occur without tangle formation.
This paradigm shift, according to which neurons are fated to degenerate once toxic tau oligomers accumulate, highlights the fact that prevention of neuronal death may require intervention at a stage earlier than NFT formation -- and that a reagent which dissolves NFTs may be in fact be terribly harmful if it leads to re-formation of toxic oligomers.
Which function of tau is crucial to neuronal health and/or compromised in neurodegeneration? Although tau was originally defined as an organizer of axonal MTs, its functions continue to expand. Tau is now known to be involved in kinesin-dependent axonal transport (Morfini et al., 2009
) and in signal transduction in dendritic spines, in connection with the interaction of kinase fyn (which phosphorylates tau on Tyr18) with NMDA receptors (Ittner and Götz, 2011
). Synapse loss and disruption of axonal transport are both early events in neurodegeneration that occur in advance or in the absence of NFT formation. Association of tau with the membrane appears to be equally crucial during neuronal development, as tau is then found in the growth cones of extending neurites which exclude MTs via a complex actin-based “shield” (Gordon-Weeks, 1993
The prevailing paradigm of tau conformation has also changed, from the traditional view of it as a coil-coil protein to increasing evidence that it normally exists in a paperclip configuration that unravels during neurodegeneration (Jeganathan et al., 2006
). This places tau in the lengthening list of proteins that may cause neuronal damage by accumulation of misfolded aggregates, from amyloid to prions.
Is tau inherently toxic in late life? Between the mild phenotype of tau null mice (although they would clearly fare poorly in the wild) and the decrease of amyloid-mediated toxicity upon tau removal (Denk and Wade-Martins, 2009
; LaFerla, 2010
), some researchers are starting to argue that we might be better off without tau in late life. However, the deficits in human pedigrees with tau microdeletions and the human-specific aspects of tau (discussed in the next section) should give us pause before we contemplate large-scale alterations to our brain/mind.