Proteostasis of polyglutamine varies among neurons and predicts neurodegeneration

ABSTRACT In polyglutamine (polyQ) diseases, only certain neurons die, despite widespread expression of the offending protein. PolyQ expansion may induce neurodegeneration by impairing

proteostasis, but protein aggregation and toxicity tend to confound conventional measurements of protein stability. Here, we used optical pulse labeling to measure effects of polyQ

expansions on the mean lifetime of a fragment of huntingtin, the protein that causes Huntington's disease, in living neurons. We show that polyQ expansion reduced the mean lifetime of

mutant huntingtin within a given neuron and that the mean lifetime varied among neurons, indicating differences in their capacity to clear the polypeptide. We found that neuronal longevity

is predicted by the mean lifetime of huntingtin, as cortical neurons cleared mutant huntingtin faster and lived longer than striatal neurons. Thus, cell type–specific differences in turnover

capacity may contribute to cellular susceptibility to toxic proteins, and efforts to bolster proteostasis in Huntington's disease, such as protein clearance, could be neuroprotective.

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support SIMILAR CONTENT BEING VIEWED BY OTHERS POLYGLUTAMINE-MEDIATED RIBOTOXICITY DISRUPTS PROTEOSTASIS AND STRESS RESPONSES IN HUNTINGTON’S DISEASE Article 13 May 2024 PERIPHERAL

SEQUESTRATION OF HUNTINGTIN DELAYS NEURONAL DEATH AND DEPENDS ON N-TERMINAL UBIQUITINATION Article Open access 18 August 2024 OSMOLYTES DYNAMICALLY REGULATE MUTANT HUNTINGTIN AGGREGATION AND

CREB FUNCTION IN HUNTINGTON’S DISEASE CELL MODELS Article Open access 23 September 2020 REFERENCES * Han, I., You, Y., Kordower, J.H., Brady, S.T. & Morfini, G.A. Differential

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http://dx.doi.org/10.1101/pdb.prot5107 (2008). Download references ACKNOWLEDGEMENTS This work was supported by grants R01 3NS039746 and 2R01 NS045191 from the US National Institute of

Neurological Disease and Stroke; grant P01 2AG022074 from the National Institute on Aging; by the Huntington's Disease Society of America (made possible with a gift from the James E.

Bashaw Family); the Taube-Koret Center for Neurodegenerative disease and the Gladstone Institutes (S.F.); the Milton Wexler Award and a fellowship from the Hereditary Disease Foundation

(A.S.T.); a fellowship from the Hillblom Foundation (M.A.); a fellowship from California Institute for Regenerative Medicine (P.S.), and in part by DMS-0914906 from the US National Science

Foundation (B.A.S.). Gladstone Institutes received support from a US National Center for Research Resources Grant RR18928-01. We thank Y. Dabaghian, I. Kelmanson, A. Gelfand and members of

the Finkbeiner laboratory for helpful discussions. The animal care facility was partly supported by a US National Institutes of Health Extramural Research Facilities Improvement Project (C06

RR018928). K. Nelson provided administrative assistance, and G.C. Howard, A.L. Lucido and S. Ordway edited the manuscript. AUTHOR INFORMATION Author notes * Montserrat Arrasate Present

address: Present address: Division of Neuroscience, Center for Applied Medical Research, University of Navarra, Pamplona, Spain., AUTHORS AND AFFILIATIONS * Gladstone Institute of

Neurological Disease, San Francisco, California, USA Andrey S Tsvetkov, Montserrat Arrasate, Sami Barmada, Punita Sharma & Steven Finkbeiner * Taube-Koret Center for Neurodegenerative

Disease Research, San Francisco, California, USA Andrey S Tsvetkov, Montserrat Arrasate, Punita Sharma & Steven Finkbeiner * Biomedical Sciences Graduate Program, University of

California–San Francisco, San Francisco, California, USA D Michael Ando & Steven Finkbeiner * Department of Statistical Science, Duke University, Durham, North Carolina, USA Benjamin A

Shaby * Graduate Programs in Neuroscience and Biomedical Sciences, University of California–San Francisco, San Francisco, California, USA Steven Finkbeiner * Program in Biological Sciences

and Medical Scientist Training Program, University of California–San Francisco, San Francisco, California, USA Steven Finkbeiner * Department of Neurology and Physiology, University of

California–San Francisco, San Francisco, California, USA Steven Finkbeiner Authors * Andrey S Tsvetkov View author publications You can also search for this author inPubMed Google Scholar *

Montserrat Arrasate View author publications You can also search for this author inPubMed Google Scholar * Sami Barmada View author publications You can also search for this author inPubMed 

Google Scholar * D Michael Ando View author publications You can also search for this author inPubMed Google Scholar * Punita Sharma View author publications You can also search for this

author inPubMed Google Scholar * Benjamin A Shaby View author publications You can also search for this author inPubMed Google Scholar * Steven Finkbeiner View author publications You can

also search for this author inPubMed Google Scholar CONTRIBUTIONS A.S.T., M.A. and S.F. designed the study. A.S.T. and S.F. wrote the manuscript. B.A.S. performed statistical analysis and

wrote the statistical analysis section of the manuscript. A.S.T., M.A., P.S., S.B. and D.M.A. wrote scripts for automated photoswitching and imaging. A.S.T. cloned all of the constructs used

in the study. A.S.T. and M.A. cultured primary neurons and performed transfections, automated microscopy, fluorescence intensity measurements and data analysis. A.S.T. performed detergent

extraction, metabolic labeling and photobleaching experiments. A.S.T. and P.S. performed survival analyses. CORRESPONDING AUTHOR Correspondence to Steven Finkbeiner. ETHICS DECLARATIONS

COMPETING INTERESTS The authors declare no competing financial interests. SUPPLEMENTARY INFORMATION SUPPLEMENTARY TEXT AND FIGURES Supplementary Results and Supplementary Figures 1–6. (PDF

1333 kb) RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Tsvetkov, A., Arrasate, M., Barmada, S. _et al._ Proteostasis of polyglutamine varies among

neurons and predicts neurodegeneration. _Nat Chem Biol_ 9, 586–592 (2013). https://doi.org/10.1038/nchembio.1308 Download citation * Received: 24 September 2012 * Accepted: 25 June 2013 *

Published: 21 July 2013 * Issue Date: September 2013 * DOI: https://doi.org/10.1038/nchembio.1308 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this

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