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Abstract
Protein aggregation is a hallmark of several neurodegenerative diseases including
Huntington's disease. We describe the use of the recently developed number and brightness
method (N&B) that uses confocal images to monitor aggregation of Huntingtin exon 1
protein (Httex1p) directly in living cells. N&B measures the molecular brightness
of protein aggregates in the entire cell noninvasively based on intensity fluctuations
at each pixel in an image. N&B applied to mutant Httex1p in living cells showed a
two-step pathway leading to inclusion formation that is polyQ length dependent and
involves four phases. An initial phase of monomer accumulation is followed by formation
of small oligomers (5-15 proteins); as protein concentration increases, an inclusion
is seeded and forms in the cytoplasm; the growing inclusion recruits most of the Httex1p
and depletes the cell leaving only a low concentration of monomers. The behavior of
Httex1p in COS-7 and ST14A cells is compared.
(c) 2010 Biophysical Society. Published by Elsevier Inc. All rights reserved.