MRC National Institute for Medical Research, London
Science for Health
Investigating function and pathogenesis of Ataxin 1
23 December 2009
Ataxin-1 (Atx1) is a member of the polyglutamine protein family. It contains regions consisting of several repeated glutamine units, called polyQ tracts, which are related to neurodegenerative diseases. These pathologies, although clinically distinct, are all caused by a common mechanism: when the number of repeats in the polyQ tract is increased above a threshold, which varies for each disease, the polyQ protein misfolds and forms aggregates leading to cellular death. In Atx1, expansion above 35-42 glutamines is associated with spinocerebellar ataxia type 1 (SCA1), a neurodegenerative disorder characterized by motor coordination deficits caused by progressive loss of Purkinje cells in the cerebellar cortex and neurons in the brain stem and spinocerebellar tracts. A causative link between polyQ expansion and the disease process is now generally accepted.
The importance of other regions of the carrier proteins has been increasingly appreciated in the past few years. It is also thought that SCA1 pathology depends on the alteration of native protein interactions, rather than on new aberrant interactions mediated by polyQ. Atx1 regions other than the polyQ tract have been functionally and structurally characterized and shown to mediate native protein-protein interactions, and to modulate the process of aggregation and pathogenesis. The molecular basis of SCA1 pathogenesis was further unravelled when it was shown that expansion of the polyQ tract is necessary but not sufficient to cause pathology. A number of other regions of the protein are also important determinants of whether disease occurs.
Annalisa Pastore (pictured) and her group in NIMR's Division of Molecular Structure, in collaboration with Toby Gibson of the European Molecular Biology Laboratory in Heidelberg, has studied in more detail the mechanisms which determine Atx1 interactions. They found that Atx1 contains a motif previously identified in splicing factors. It overlaps with a region of the protein that binds the regulatory protein 14-3-3, and also overlaps with the nuclear localization signal. They demonstrated that phosphorylation of S776 within the motif plays a key role, providing a molecular switch which discriminates between 14-3-3 and components of the spliceosome. They concluded that rather than a simplistic gain- or loss-of-function mechanism, SCA1 pathology is triggered by complex alterations of its normal interactions, some of which even exert a protective role against disease.
Schematic model of the cellular interactions formed by Atx1 and the role of phosphorylation in pathology
S776 phosphorylation would be at the crossing point of two different pathways. When Atx1 (blue oval) is not phosphorylated, it interacts with the spliceosome (light blue shape) and is protected from aggregation. Phosphorylated Atx1 has higher affinity to 14-3-3 proteins but is not protected against self-association. In vitro, the Ala mutant mimics correctly the properties of non-phosphorylated Atx1, whereas the Asp mutant, which has properties very different from the phosphorylated sequence, is not recognized by 14-3-3.
A key point that becomes clear from our studies is the importance of investigating the non-pathologic molecular interactions as a strategy to identify mechanisms that prevent aggregation. Also, it is clear that it is far too simplistic to approach SCA1 or other polyQ diseases in terms of a gain or loss-of-function. These concepts are particularly inadequate when function is described in terms of enhanced or reduced interactions and strongly depend on which of the several interactions we may refer to. PolyQ proteins take part in a complex and vast network of interactions, to which polyQ aggregation adds another competing pathway. For complex regulatory systems, the difficult balance of multiple equilibria can only be appropriately described by gaining an overall picture which places each interaction into the bigger frame of everything known about the individual components. Studies of the interactions formed by non-expanded Atx1 thus provide valuable hints for understanding both the function of the non-pathologic protein and the causes of the disease.
Annalisa Pastore
Original article
The research findings are published in full in:
Cesira de Chiara, Rajesh P. Menon, Molly Strom, Toby J. Gibson and Annalisa Pastore (2009)
Phosphorylation of S776 and 14-3-3 binding modulate Ataxin 1 interaction with splicing factors
PLoS ONE, 4(12): e8372 Publisher fulltext
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