Engineering enhanced protein disaggregases for neurodegenerative disease

Prion
Meredith E Jackrel, James Shorter

Abstract

Protein misfolding and aggregation underpin several fatal neurodegenerative diseases, including Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD). There are no treatments that directly antagonize the protein-misfolding events that cause these disorders. Agents that reverse protein misfolding and restore proteins to native form and function could simultaneously eliminate any deleterious loss-of-function or toxic gain-of-function caused by misfolded conformers. Moreover, a disruptive technology of this nature would eliminate self-templating conformers that spread pathology and catalyze formation of toxic, soluble oligomers. Here, we highlight our efforts to engineer Hsp104, a protein disaggregase from yeast, to more effectively disaggregate misfolded proteins connected with PD, ALS, and FTD. Remarkably subtle modifications of Hsp104 primary sequence yielded large gains in protective activity against deleterious α-synuclein, TDP-43, FUS, and TAF15 misfolding. Unusually, in many cases loss of amino acid identity at select positions in Hsp104 rather than specific mutation conferred a robust therapeutic gain-of-function. Nevertheless, the misfolding and toxicity of EWSR1, an RNA-binding ...Continue Reading

References

Jun 1, 1990·Science·Y Sanchez, S L Lindquist
Dec 1, 1994·Nature·D A ParsellS Lindquist
May 17, 2000·Proceedings of the National Academy of Sciences of the United States of America·S H SatyalR I Morimoto
Jun 12, 2002·The Journal of Cell Biology·Anatoli B MeriinMichael Y Sherman
Jan 1, 2003·Cell·Jue D WangJonathan S Weissman
Nov 1, 2003·Science·A B SingletonK Gwinn-Hardy
Dec 6, 2003·Science·Tiago Fleming Outeiro, Susan Lindquist
Feb 3, 2004·Annals of Neurology·Juan J ZarranzJusto G de Yebenes
Feb 24, 2004·Molecular Biology of the Cell·Eric C SchirmerSusan Lindquist
May 7, 2004·The Journal of Biological Chemistry·Ronnie LumJohn R Glover
Sep 29, 2004·Lancet·Marie-Christine Chartier-HarlinAlain Destée
Apr 13, 2005·The Journal of Biological Chemistry·Kavita C GokhaleYury O Chernoff
Jun 3, 2005·Nature Reviews. Genetics·James Shorter, Susan Lindquist
Aug 25, 2005·Cold Spring Harbor Symposia on Quantitative Biology·K SiE Kandel
Nov 23, 2005·PLoS Biology·Douglas M FowlerJeffery W Kelly
Jul 13, 2006·Proceedings of the National Academy of Sciences of the United States of America·Martin L DuennwaldSusan Lindquist
Nov 4, 2006·Science·Michel Goedert, Maria Grazia Spillantini
Jan 30, 2007·Nature Structural & Molecular Biology·Shannon M DoyleSue Wickner
Mar 28, 2007·Journal of Neuroscience Research·Shona L OsborneFrederic A Meunier
Apr 7, 2007·Trends in Biochemical Sciences·Douglas M FowlerJeffery W Kelly
Dec 22, 2007·Neuro-Signals·James Shorter
Feb 22, 2008·Annals of Neurology·Michael A GitchoNigel J Cairns
Mar 1, 2008·Science·Jemeen SreedharanChristopher E Shaw
Apr 25, 2008·Proceedings of the National Academy of Sciences of the United States of America·Brian S JohnsonAaron D Gitler
May 20, 2008·Nature Structural & Molecular Biology·Tobias HaslbergerBernd Bukau
Aug 16, 2008·The Journal of Clinical Investigation·Christophe Lo BiancoPatrick Aebischer
Aug 30, 2008·The Journal of Biological Chemistry·Ronnie LumJohn R Glover
Nov 26, 2008·The Journal of Cell Biology·John J SkinnerBen E Black

❮ Previous
Next ❯

Citations

Aug 22, 2015·Chemistry & Biology·Eva AspRajaraman Krishnan
Aug 11, 2015·Chemistry & Biology·Laura M CastellanoJames Shorter
Nov 27, 2015·Journal of Molecular Biology·Elizabeth A Sweeny, James Shorter
Nov 18, 2015·Revue neurologique·J-J HauwC Duyckaerts
Mar 26, 2016·Frontiers in Molecular Biosciences·Korrie L Mack, James Shorter
Apr 8, 2016·Trends in Cell Biology·Adriano Aguzzi, Matthias Altmeyer
Jul 15, 2015·Archives of Biochemistry and Biophysics·Alejandra AguadoArturo Muga
Oct 30, 2016·RNA Biology·Francesca SvetoniMaria Paola Paronetto
Aug 16, 2016·Cellular and Molecular Life Sciences : CMLS·Sandeep K Sharma, Smriti Priya
Nov 7, 2016·Cold Spring Harbor Perspectives in Biology·Tatiana A ChernovaYury O Chernoff
Jun 28, 2017·PLoS Biology·Jeremy D BakerLaura J Blair
Jun 4, 2016·Molecular Biology of the Cell·James Shorter
May 23, 2018·FEMS Yeast Research·Amber TariqJames Shorter
Jun 7, 2019·The Journal of Biological Chemistry·Jeremy J RyanMeredith E Jackrel
Apr 9, 2017·The Biochemical Journal·Alice Ford Harrison, James Shorter
Dec 29, 2019·The Journal of Biological Chemistry·Elizabeth A SweenyJames Shorter
Mar 11, 2020·PloS One·Matthew K HowardMeredith E Jackrel
Jan 10, 2016·The Journal of Biological Chemistry·Mariana P TorrenteJames Shorter
Aug 5, 2020·Expert Opinion on Therapeutic Targets·Yiran Wang, Rickie Patani
Dec 7, 2016·Cold Spring Harbor Perspectives in Medicine·Lin Guo, James Shorter
Mar 16, 2017·Frontiers in Neuroscience·Meredith E Jackrel, James Shorter
Oct 13, 2017·Frontiers in Molecular Neuroscience·Destiny-Love ManeckaThomas M Durcan
Jan 9, 2019·Frontiers in Molecular Neuroscience·Zachary T MonahanFrank P Shewmaker
Apr 11, 2019·Frontiers in Genetics·Veronica VerdileMaria Paola Paronetto
Sep 19, 2018·Brain Sciences·Rashad HussainMuhammad Shahab
Dec 16, 2020·ELife·Zachary M MarchJames Shorter
Jan 16, 2021·Trends in Biochemical Sciences·Bede PortzJames Shorter
Feb 8, 2021·Biochimica Et Biophysica Acta. Molecular Cell Research·April L Darling, James Shorter
Jan 25, 2021·The Journal of Biological Chemistry·Elizabeth A SweenyJames Shorter
May 5, 2021·Disease Models & Mechanisms·Charlotte M Fare, James Shorter
May 20, 2021·Protein Science : a Publication of the Protein Society·Jeremy J RyanMeredith E Jackrel
Aug 7, 2021·Biomolecules·Macy L Sprunger, Meredith E Jackrel
Oct 7, 2015·ACS Chemical Biology·Meredith E JackrelJames Shorter
Sep 1, 2021·Journal of Molecular Biology·Hana M OdehJames Shorter

❮ Previous
Next ❯

Methods Mentioned

BETA
Fluorescence microscopy
environmental stresses
environmental stress

Related Concepts

Related Feeds

ALS: Genetics

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by muscle weakness. Here is the latest research investigating genetic alterations in this genetically heterogeneous disorder.

ALS & FTD: TDP-43

TAR DNA-binding protein 43 (TDP-43) is a pathological protein identified in sporadic Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD). Here are the latest discoveries pertaining to TDP-43 and these diseases.

ALS: Genetics

Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder characterized by muscle weakness. ALS is a genetically heterogeneous disorder with several causative genes. Here are the latest discoveries pertaining to the genetics of this disease.

Amyloid Lateral Sclerosis

Amyotrophic Lateral Sclerosis (ALS) is a progressive nervous system disease associated with the death of neurons that control voluntary muscles. Discover the latest research on ALS here.

ALS: Pathogenic Mechanisms

Amyotrophic Lateral Sclerosis is a progressive neurodegenerative disorder characterized by muscle weakness. Here is the latest research investigating pathogenic mechanisms that underlie this genetically heterogeneous disorder.