Wheeler JM, McMillan P, Strovas TJ, Liachko NF, Amlie-Wolf A, Kow RL, Klein RL, Szot P, Robinson L, Guthrie C, Saxton A, Kanaan NM, Raskind M, Peskind E, Trojanowski JQ, Lee VM, Wang LS, Keene CD, Bird T, Schellenberg GD, Kraemer B. Activity of the poly(A) binding protein MSUT2 determines susceptibility to pathological tau in the mammalian brain. Sci Transl Med. 2019 Dec 18;11(523) PubMed.
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DZNE (German Center for Neurodegenerative Diseases)
"Tau factor" was initially described by Marc Kirschner and colleagues as a protein promoting the assembly of microtubules (MT) in neurons (Weingarten et al., 1975). Within the same year Joe Bryan and colleagues showed that tau also interacts strongly with RNA, in competition with microtubules (Bryan et al., 1975). Since then, we have come to know that tau interacts with dozens of cellular proteins and nucleic acids, including many cytoskeletal proteins and RNAs. This can be explained by tau's natively unfolded, hydrophilic, and basic character, which exposes multiple binding sites, preferentially with acidic polymers such as microtubules or RNA.
Subsequently, it was found that tau is also a key component of one of the two types of proteinaceous deposits that characterize the brains of patients with Alzheimer Disease, known as "neurofibrillary tangles" (Grundke-Iqbal et al., 1986). The push by the biomedical community to understand and alleviate AD led to numerous publications on tau protein, a large fraction of them dealing with tau's interactions with microtubules and the implications for neuronal pathology in AD (currently 2,846 entries for tauµtubules in Pubmed).
By comparison, studies on interactions between tau and RNA remained at a low level (currently 49 entries for tau&RNA), in spite of early reports of tau in nuclei and on ribosomes (Skip Binder's group, e.g. Loomis et al., 1990) and our observation that RNA can trigger the aggregation of tau into paired helical filaments (Kampers et al., 1996). This situation changed in recent years, notably with the realization that cell stress-induced granules in the cytoplasm contain tau in combination with RNA (e.g. Ben Wolozin's group, Vanderweyde et al., 2016) and with Ken Kosik’s, Songi Han’s, and Markus Zweckstetter’s groups demonstrating that tau plus RNA can drive liquid-liquid phase separation (e.g. Zhang et al., 2017; Ambadipudi et al., 2017).
This new paper reveals an intriguing new interplay between RNA, tau, and other RNA-binding proteins. One remarkable aspect is that neither MSUT2 nor its cousin SUT-1 (also discovered by the same group, Kraemer and Schellenberg, 2007) has an obvious relationship with microtubules, even though both are required to generate tau pathology, and both are localized primarily in the nucleus, with only small amounts shuttling to the cytoplasm where they could interact with microtubules.
In the case of MSUT2, the findings emphasize a mechanism of length control of the 3'UTR of mRNAs by the interaction between proteins MSUT2 and PABPN1. A proper length of the poly(A) tail is necessary for subsequent translation into protein by ribosomes; overactivity of MSUT2 reduces the length of the poly(A) tail, overactivity of PABPN1 increases it. When the tail is too short (overactive MSUT2), this results in the onset of the hallmarks of tau pathology—aberrant phosphorylation, conformation, and aggregation. Thus MSUT2 enables the pathology of tau, which seems somewhat counterintuitive considering its name (SUT stands for suppressor of tau pathology), but in keeping with conventions in the worm field.
In spite of these advances, the exact pathway of the tau-MSUT2 interplay remains somewhat elusive. MSUT2 binds independently to poly(A) tails or to PABPN1 (which also binds to poly(A)), and both proteins colocalize with poly(A) in nuclear speckles. Given that tau can interact with RNA, the authors suspected that MSUT2 might influence the binding of tau to poly(A) tails. But this was ruled out by various controls, e.g., by varying the poly(A) tail length. There was also no change on gene expression, and the authors concluded that the SUT2/PABPN1 dimer influences tau aggregation indirectly.
One intriguing possibility is that MSUT2 might promote the formation of stress granules which also contain poly(A) binding proteins (see, e.g., Vanderweyde et al., 2016). Since the job of stress granules is to transiently halt protein synthesis, this rings a bell with a recent report that tau can interfere with the function of ribosomal proteins (Koren et al., 2019).
Is there still a role for microtubules in this scenario? The authors cite indirect links to microtubules (after all, tau still qualifies as a MAP), e.g. by analogy with other polyadenylation factors, but details remain to be clarified. Another open issue is the chain of causality: MSUT2 promotes the pathology of an aggregation-prone version of tau, however, the authors cite reports that MSUT2 or other regulators of polyadenylation may affect synapses and memory without an obvious link to tau.
The novelty of this work for neurodegeneration is highlighted by the fact that the occurrence and level of MSUT2 and its partner PABPN1 correlate tightly with AD, as judged by postmortem analysis. Tangle-bearing neurons have elevated levels of MSUT2 and appear to die prematurely, in agreement with the hypothesis that MSUT2 enables tau pathology. Related to this neuronal degeneration is the observation that MSUT2 promotes neuroinflammation (astrocytosis, microgliosis), presumably in response to pathological tau. The coincidence of neuroinflammation and tauopathy agrees well with a recent report that the activated NLRP3 inflammasome can cause tau pathology (Ising et al., 2019), although the causality is opposite in the two examples, and in case of the inflammasome the primary trigger still comes from Aβ.
As a devout tauist, one is struck by the breadth of new emerging tau functions, in the neuronal nucleus, the cytoplasm, synapses, and outside neurons. Let's hope that one of them leads to a treatment of AD, not just prevention before, but reversal after cognitive decline sets in. It can be done with mice, so there is still hope for people.
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