A Liquid to Solid Phase Transition Underlying Pathological Huntingtin Exon1 Aggregation.

Molecular Cell
Thomas R PeskettH R Saibil

Abstract

Huntington's disease is caused by an abnormally long polyglutamine tract in the huntingtin protein. This leads to the generation and deposition of N-terminal exon1 fragments of the protein in intracellular aggregates. We combined electron tomography and quantitative fluorescence microscopy to analyze the structural and material properties of huntingtin exon1 assemblies in mammalian cells, in yeast, and in vitro. We found that huntingtin exon1 proteins can form reversible liquid-like assemblies, a process driven by huntingtin's polyQ tract and proline-rich region. In cells and in vitro, the liquid-like assemblies converted to solid-like assemblies with a fibrillar structure. Intracellular phase transitions of polyglutamine proteins could play a role in initiating irreversible pathological aggregation.

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Methods Mentioned

BETA
electron
fluorescence microscopy
fluorescence recovery after photobleaching
electron microscopy
dot blots
dot blotting
electron tomography
PCR
FCS
Fluorescence

Software Mentioned

R
MATLAB
Tensorflow
jython
IMOD
SerialEM
Fiji

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