By virtue of its location, restricted evolutionary profile and allele-specific correlations with neurodegenerative diseases, STH is a truly intriguing molecule. Because of its lack of obvious motifs, its function has been elusive. Our previous work showed that STH interacts with Abl in vitro (Conrad, 2003
) and with Prdx6 in cells and in vitro in allele-specific fashion (Gao et al., 2005
). The present work establishes tau and Abl as additional STH binding partners and gives further hints to the possible role(s) that STH may play in the cell.
Among its many roles, tau promotes neurite outgrowth, organizes axonal microtubules, is involved in kinesin-dependent axonal transport and also appears to be involved in signal transduction in dendritic spines (Ittner and Götz, 2011
; Morfini et al., 2009
; Wang and Liu, 2007). Tau splicing and phosphorylation modulate tau function and the misregulation of either process results in neurofibrillary tangle formation and neurodegeneration (Andreadis, 2011
; Dolan and Johnson, 2010
). In particular, misregulation of splicing that leads to altered ratios of tau exon 10 results in tangle-only dementias (Gasparini et al., 2007
The STH interaction with tau is tantalizing, given that STH is nested in the tau locus, its expression patterns are very similar to those of tau and they partly co-localize (Conrad et al., 2002
). The region of interaction appears to be close to the C-terminus of STH. If STH were found to influence the phosphorylation of tau Tyr394 by Abl, this would establish a STH link to neurodegeneration although its exact mechanism would still need to be deciphered.
The increase of tau exon 10 inclusion in the presence of STH is more enigmatic. Since STH is cytosolic (Conrad, 2003
; Gao et al., 2005
), it must affect splicing of exon 10 by indirect mechanisms. STH might influence the localization or phosphorylation of shuttling splicing factors or their kinases, thereby modulating their activity.
Like tau, tyrosine kinase Abl also performs many roles, including DNA damage response, cell cycle regulation and actin cytoskeleton signal transduction (Moresco and Koleske, 2003
; Shaul, 2000
; Sirvent et al., 2008
). Abl phosphorylation and localization change in Alzheimer’s disease (Jing et al., 2009
). Specifically, Abl phosphorylates Tyr394 of tau and this tau species is found in neurofibrillary tangles (Derkinderen et al., 2005
; Tremblay et al., 2010
These connections make the STH/Abl reciprocal effects potentially very relevant: STH appears to be a substrate for Abl, even though its sole tyrosine is not within a canonical Abl phosphorylation sequence. It is possible that Abl affects STH phosphorylation through another tyrosine kinase. Conversely, STH increases Abl-mediated phosphorylation in allele-specific fashion, with the human-specific Q allele showing a stronger effect than the ancestral R.
As mentioned above, STH is cytosolic whereas Abl shuttles between the nucleus and the cytoplasm. One possible mechanism for the effect of STH on Abl is that STH might partition a higher proportion of Abl into the cytoplasm by binding to it. This would result in the increase of cytoplasmic tyrosine phosphorylation. In turn, tyrosine-phosphorylated STH would most likely have a modified activity profile.
A STH-induced shift would not need to be large to cause significant domino effects. In connection with this, it is interesting that our results show a large increase of STH in AD hippocampus. It will be revealing to see if STH levels also increase in tangle-only dementias. Another fascinating commonality is that the splicing regulation of tau exon 10 and the presence of a STH ORF are both species-specific, though the STH species range is far more restricted.
The evidence is circumstantial but highly suggestive that STH, through its allele-specific reciprocal interactions with Prdx6, tau and Abl, may be linked to the cascade of events which lead to neurodegeneration. Chimpanzees, which exclusively have the STH R allele, appear resistant to neurodegeneration whereas the Q allele confers susceptibility to several tangle-only dementias (Conrad, 2002
; Andreadis, 2011
). In view of this, it is odd that the ancestral R allele is rare in humans. Perhaps STHQ confers an advantage during development and early life but becomes detrimental in later life. The fact that STH Q allele is unique to humans makes it an invaluable tool to understanding why dementia seems to have singled out our species for preferential treatment.