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Proteasome-targeted nanobodies alleviate pathology and functional decline in an α-synuclein-based Parkinson's disease model.

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cam.issuedOnline2018-08-22
dc.contributor.authorChatterjee, Diptaman
dc.contributor.authorBhatt, Mansi
dc.contributor.authorButler, David
dc.contributor.authorDe Genst, Erwin
dc.contributor.authorDobson, Christopher M
dc.contributor.authorMesser, Anne
dc.contributor.authorKordower, Jeffrey H
dc.date.accessioned2018-11-22T00:32:03Z
dc.date.available2018-11-22T00:32:03Z
dc.date.issued2018
dc.description.abstractTherapeutics designed to target α-synuclein (α-syn) aggregation may be critical in halting the progression of pathology in Parkinson's disease (PD) patients. Nanobodies are single-domain antibody fragments that bind with antibody specificity, but allow readier genetic engineering and delivery. When expressed intracellularly as intrabodies, anti-α-syn nanobodies fused to a proteasome-targeting proline, aspartate or glutamate, serine, and threonine (PEST) motif can modulate monomeric concentrations of target proteins. Here we aimed to validate and compare the in vivo therapeutic potential of gene therapy delivery of two proteasome-directed nanobodies selectively targeting α-syn in a synuclein overexpression-based PD model: VH14*PEST (non-amyloid component region) and NbSyn87*PEST (C-terminal region). Stereotaxic injections of adeno-associated viral 5-α-syn (AAV5-α-syn) into the substantia nigra (SN) were performed in Sprague-Dawley rats that were sorted into three cohorts based on pre-operative behavioral testing. Rats were treated with unilateral SN injections of vectors for VH14*PEST, NbSyn87*PEST, or injected with saline 3 weeks post lesion. Post-mortem assessments of the SN showed that both nanobodies markedly reduced the level of phosphorylated Serine-129 α-syn labeling relative to saline-treated animals. VH14*PEST showed considerable maintenance of striatal dopaminergic tone in comparison to saline-treated and NbSyn87*PEST-treated animals as measured by tyrosine hydroxylase immunoreactivity (optical density), DAT immunoreactivity (optical density), and dopamine concentration (high-performance liquid chromatography). Microglial accumulation and inflammatory response, assessed by stereological counts of Iba-1-labeled cells, was modestly increased in NbSyn87*PEST-injected rats but not in VH14*PEST-treated or saline-treated animals. Modest behavioral rescue was also observed, although there was pronounced variability among individual animals. These data validate in vivo therapeutic efficacy of vector-delivered intracellular nanobodies targeting α-syn misfolding and aggregation in synucleinopathies such as PD.
dc.format.mediumElectronic-eCollection
dc.identifier.doi10.17863/CAM.32997
dc.identifier.eissn2373-8057
dc.identifier.issn2373-8057
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/285645
dc.languageeng
dc.language.isoeng
dc.publisherSpringer Science and Business Media LLC
dc.publisher.urlhttp://dx.doi.org/10.1038/s41531-018-0062-4
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subject1109 Neurosciences
dc.subjectBiomedical
dc.subjectBasic Science
dc.subjectGene Therapy
dc.subjectAging
dc.subjectNeurosciences
dc.subjectDementia
dc.subjectNeurodegenerative
dc.subjectGenetics
dc.subjectBrain Disorders
dc.subjectParkinson's Disease
dc.subjectAcquired Cognitive Impairment
dc.subjectBiotechnology
dc.subjectNeurological
dc.subject2.1 Biological and endogenous factors
dc.titleProteasome-targeted nanobodies alleviate pathology and functional decline in an α-synuclein-based Parkinson's disease model.
dc.typeArticle
dcterms.dateAccepted2018-07-11
prism.publicationDate2018
prism.publicationNameNPJ Parkinsons Dis
prism.startingPage25
prism.volume4
rioxxterms.licenseref.startdate2018-01
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.typeJournal Article/Review
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1038/s41531-018-0062-4

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