In this work we investigate subcellular localization and proteolytic cleavage of different forms of ataxin-3 (AT-3), the protein responsible for spinocerebellar ataxia type 3. Normal (AT-3Q6 and AT-3Q26) and pathological (AT-3Q72) ataxins-3, as well as two truncated forms lacking poly-Q, were studied. Full-length proteins were also expressed as C14A mutants, in order to assess whether AT-3 autoproteolytic activity was involved in its fragmentation. We found that both normal and pathological proteins localized in the cytoplasm and in the nucleus, as expected, but also in the mitochondria. Microsequencing showed that all ataxins-3 underwent the same proteolytic cleavage, removing the first 27 aminoacids. Interestingly, while normal ataxins were further cleaved at a number of caspase sites, pathological AT-3 was proteolyzed to a much lesser extent. This may play a role in the pathogenesis, hampering degradation of aggregation-prone expanded AT-3. In addition, autolytic cleavage was apparently not involved in AT-3 proteolysis.

Study of subcellular localization and proteolysis of ataxin-3 / C. Pozzi, M. Valtorta, G. Tedeschi, E. Galbusera, V. Pastori, A. Bigi, S. Nonnis, E. Grassi, P. Fusi. - In: NEUROBIOLOGY OF DISEASE. - ISSN 0969-9961. - 30:2(2008 May), pp. 190-200.

Study of subcellular localization and proteolysis of ataxin-3

M. Valtorta
Secondo
;
G. Tedeschi;S. Nonnis;E. Grassi
Penultimo
;
2008

Abstract

In this work we investigate subcellular localization and proteolytic cleavage of different forms of ataxin-3 (AT-3), the protein responsible for spinocerebellar ataxia type 3. Normal (AT-3Q6 and AT-3Q26) and pathological (AT-3Q72) ataxins-3, as well as two truncated forms lacking poly-Q, were studied. Full-length proteins were also expressed as C14A mutants, in order to assess whether AT-3 autoproteolytic activity was involved in its fragmentation. We found that both normal and pathological proteins localized in the cytoplasm and in the nucleus, as expected, but also in the mitochondria. Microsequencing showed that all ataxins-3 underwent the same proteolytic cleavage, removing the first 27 aminoacids. Interestingly, while normal ataxins were further cleaved at a number of caspase sites, pathological AT-3 was proteolyzed to a much lesser extent. This may play a role in the pathogenesis, hampering degradation of aggregation-prone expanded AT-3. In addition, autolytic cleavage was apparently not involved in AT-3 proteolysis.
Settore BIO/10 - Biochimica
mag-2008
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/54898
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