title: Protein misfolding in neurodegenerative diseases: implications and strategies.
abstract: A hallmark of neurodegenerative proteinopathies is the formation of misfolded protein aggregates that cause cellular toxicity and contribute to cellular proteostatic collapse. Therapeutic options are currently being explored that target different steps in the production and processing of proteins implicated in neurodegenerative disease, including synthesis, chaperone-assisted folding and trafficking, and degradation via the proteasome and autophagy pathways. Other therapies, like mTOR inhibitors and activators of the heat shock response, can rebalance the entire proteostatic network. However, there are major challenges that impact the development of novel therapies, including incomplete knowledge of druggable disease targets and their mechanism of action as well as a lack of biomarkers to monitor disease progression and therapeutic response. A notable development is the creation of collaborative ecosystems that include patients, clinicians, basic and translational researchers, foundations and regulatory agencies to promote scientific rigor and clinical data to accelerate the development of therapies that prevent, reverse or delay the progression of neurodegenerative proteinopathies.
authors.affiliation: Discovery Services, Charles Rivers Laboratories, Wilmington, MA USA.|Royal Veterinary College, University of London, London, UK.
authors.forename: Patrick
authors.initials: P
authors.lastname: Sweeney
authors.affiliation: Health & Life Science Consulting, Los Angeles, CA USA.
authors.forename: Hyunsun
authors.initials: H
authors.lastname: Park
authors.affiliation: Biochemistry and Developmental Biology, University of Helsinki, Helsinki, Finland.
authors.forename: Marc
authors.initials: M
authors.lastname: Baumann
authors.affiliation: Neuroscience Innovation Medicines, Astra Zeneca, Cambridge, MA USA.
authors.forename: John
authors.initials: J
authors.lastname: Dunlop
authors.affiliation: Stanford University, Stanford, CA USA.
authors.forename: Judith
authors.initials: J
authors.lastname: Frydman
authors.affiliation: Stanford University, Stanford, CA USA.
authors.forename: Ron
authors.initials: R
authors.lastname: Kopito
authors.affiliation: Neurology, Biogen Idec, Cambridge, MA USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: McCampbell
authors.affiliation: Leblanc Bioscience Consulting, Berkeley, CA USA.
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Leblanc
authors.affiliation: Discovery Services, Charles Rivers Laboratories, Wilmington, MA USA.
authors.forename: Anjli
authors.initials: A
authors.lastname: Venkateswaran
authors.affiliation: Discovery Services, Charles Rivers Laboratories, Wilmington, MA USA.
authors.forename: Antti
authors.initials: A
authors.lastname: Nurmi
authors.affiliation: Discovery Services, Charles Rivers Laboratories, Wilmington, MA USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Hodgson
keywords: Biomarkers; Chaperones; Drug discovery; Mouse models; Neurodegeneration; Proteostasis