Delayed emergence of subdiffraction-sized mutant huntingtin fibrils following inclusion body formation

Quarterly Reviews of Biophysics
Steffen J SahlW E Moerner

Abstract

Aberrant aggregation of improperly folded proteins is the hallmark of several human neurodegenerative disorders, including Huntington's Disease (HD) with autosomal-dominant inheritance. In HD, expansion of the CAG-repeat-encoded polyglutamine (polyQ) stretch beyond ~40 glutamines in huntingtin (Htt) and its N-terminal fragments leads to the formation of large (up to several μm) globular neuronal inclusion bodies (IBs) over time. We report direct observations of aggregating Htt exon 1 in living and fixed cells at enhanced spatial resolution by stimulated emission depletion (STED) microscopy and single-molecule super-resolution optical imaging. Fibrils of Htt exon 1 arise abundantly across the cytosolic compartment and also in neuritic processes only after nucleation and aggregation into a fairly advanced stage of growth of the prominent IB have taken place. Structural characterizations of fibrils by STED show a distinct length cutoff at ~1·5 µm and reveal subsequent coalescence (bundling/piling). Cytosolic fibrils are observed even at late stages in the process, side-by-side with the mature IB. Htt sequestration into the IB, which in neurons has been argued to be a cell-protective phenomenon, thus appears to saturate and over-po...Continue Reading

References

Apr 14, 1999·Proceedings of the National Academy of Sciences of the United States of America·E ScherzingerE E Wanker
Nov 1, 2001·Proceedings of the National Academy of Sciences of the United States of America·R S RajanR R Kopito
Aug 13, 2002·The Journal of Biological Chemistry·Michelle A PoirierChristopher A Ross
Apr 10, 2007·Annual Review of Neuroscience·Harry T Orr, Huda Y Zoghbi
Aug 1, 2007·Proceedings of the National Academy of Sciences of the United States of America·W E Moerner
Oct 24, 2007·Nature Methods·Katrin I WilligStefan W Hell
Dec 13, 2007·Optics Letters·T A Klar, S W Hell
Dec 22, 2007·Biophysical Journal·Michelle A DigmanEnrico Gratton
Mar 10, 2009·Nature Structural & Molecular Biology·Ashwani K ThakurRonald Wetzel
Jan 9, 2010·Journal of Microscopy·S WolterM Sauer
Mar 12, 2010·The Journal of Biological Chemistry·Justin LegleiterPaul J Muchowski
Dec 18, 2010·Lancet Neurology·Christopher A Ross, Sarah J Tabrizi
Jul 8, 2011·Chemphyschem : a European Journal of Chemical Physics and Physical Chemistry·Whitney C DuimW E Moerner
Feb 4, 2012·Science·Sebastian BerningStefan W Hell
Jun 28, 2012·Biophysical Journal·Laura PieriRonald Melki
Jan 24, 2013·Proceedings of the National Academy of Sciences of the United States of America·Kirupa SathasivamGillian P Bates
Feb 1, 2013·Proceedings of the National Academy of Sciences of the United States of America·Emily M SontagLeslie M Thompson
Aug 13, 2013·Current Opinion in Structural Biology·Steffen J Sahl, W E Moerner
Dec 3, 2013·Journal of Molecular Biology·Karunakar KarRonald Wetzel
Mar 7, 2014·The Journal of Biological Chemistry·Elizabeth Landrum, Ronald Wetzel
Jun 13, 2014·Biochemistry·Bankanidhi SahooRonald Wetzel
Aug 19, 2014·Essays in Biochemistry·Ko-Fan Chen, Damian C Crowther
Aug 19, 2014·Essays in Biochemistry·Philipp TrepteErich E Wanker
Jan 1, 2015·Nature Reviews. Disease Primers·Gillian P BatesSarah J Tabrizi

❮ Previous
Next ❯

Citations

Feb 9, 2017·Biochemistry·Adewale AdegbuyiroJustin Legleiter
Mar 7, 2017·Chemical Reviews·Hans Blom, Jerker Widengren
Sep 7, 2017·Nature Reviews. Molecular Cell Biology·Steffen J SahlStefan Jakobs
Jun 27, 2016·Methods and Applications in Fluorescence·Romain F LaineClemens F Kaminski
Jul 16, 2020·Nanoscale·Joaquim TorraCristina Flors
Aug 2, 2018·Frontiers in Neuroscience·Youjoung KimEvon S Ereifej
Apr 8, 2017·Frontiers in Neuroscience·E F E KuiperSteven Bergink
Mar 24, 2021·Chemical Reviews·Christian WernerChristian Geis
Apr 9, 2020·Molecular Cell·Willianne I M VonkJudith Frydman
Dec 28, 2019·ACS Chemical Neuroscience·Faezeh SedighiJustin Legleiter

❮ Previous
Next ❯

Methods Mentioned

BETA
fluorescence microscopy
super-resolution microscopy
transfection

Software Mentioned

RapidSTORM

Related Concepts

Related Feeds

BioHub - Researcher Network

The Chan-Zuckerberg Biohub aims to support the fundamental research and develop the technologies that will enable physicians to cure, prevent, or manage all diseases in our childrens' lifetimes. The CZ Biohub brings together researchers from UC Berkeley, Stanford, and UCSF. Find the latest research from the CZ Biohub researcher network here.