Mapping the self-association domains of ataxin-1: identification of novel non overlapping motifs.
The neurodegenerative disease spinocerebellar ataxia type 1 (SCA1) is caused by aggregation and misfolding of the ataxin-1 protein. While the pathology correlates with mutations that lead to expansion of a polyglutamine tract in the protein, other regions contribute to the aggregation process as also non-expanded ataxin-1 is intrinsically aggregation-prone and forms nuclear foci in cell. Here, we have used a combined approach based on FRET analysis, confocal microscopy and in vitro techniques to map aggregation-prone regions other than polyglutamine and to establish the importance of dimerization in self-association/foci formation. Identification of aggregation-prone regions other than polyglutamine could greatly help the development of SCA1 treatment more specific than that based on targeting the low complexity polyglutamine region.
MRC National Institute for Medical Research, The Ridgeway , London , UK.
Rajesh P
RP
Menon
Randall Division for Cell and Molecular Biophysics, New Hunt's House, King's College London , Guy's Campus, London , UK ; British Heart Foundation Centre of Research Excellence, King's College London , Denmark Hill Campus, London , UK.
Daniel
D
Soong
MRC National Institute for Medical Research, The Ridgeway , London , UK.
Cesira
C
de Chiara
Randall Division for Cell and Molecular Biophysics, New Hunt's House, King's College London , Guy's Campus, London , UK.
Mark
M
Holt
MRC National Institute for Medical Research, The Ridgeway , London , UK.
John E
JE
McCormick
British Heart Foundation Centre of Research Excellence, King's College London , Denmark Hill Campus, London , UK.
Narayana
N
Anilkumar
MRC National Institute for Medical Research, The Ridgeway , London , UK ; Department of Molecular Neuroscience, Institute of Psychiatry, King's College London , Denmark Hill Campus, London , UK.
Annalisa
A
Pastore
Confocal microscopy; FRET; Foci; Misfolding diseases; Spinocerebellar ataxia type 1