title: Transcriptional activity of novel ALDH1L1 promoters in the rat brain following AAV vector-mediated gene transfer.
abstract: Aldehyde dehydrogenase family 1, member L1 (ALDH1L1) is a recently characterized pan-astrocytic marker that is more homogenously expressed throughout the brain than the classic astrocytic marker, glial fibrillary acidic protein. We generated putative promoter sequence variants of the ratALDH1L1gene for use in adeno-associated viral vector-mediated gene transfer, with an aim to achieve selective regulation of transgene expression in astrocytes in the rat brain. Unexpectedly, ALDH1L1 promoter variants mediated transcriptional activity exclusively in neurons in the substantia nigra pars compacta as assessed by luciferase reporter expression at 3 weeks postvector infusion. This selectivity for neurons in the substantia nigra pars compacta also persisted in the context of adeno-associated viral serotype 5, 8 or 9 vector-mediated gene delivery. Anin vivopromoter comparison showed the highest performing ALDH1L1 promoter variant mediated higher transgene expression than the neuronal-specific synapsin 1 and tyrosine hydroxylase promoters. The ALDH1L1 promoter was also transcriptionally active in dentate granule neurons following intrahippocampal adeno-associated viral vector infusion, whereas transgene expression was detected in both striatal neurons and astrocytes following vector infusion into the striatum. Our results demonstrate the potential suitability of the ALDH1L1 promoter as a new tool in the development of gene therapy and disease modelling applications.
authors.affiliation: Department of Pharmacology and Clinical Pharmacology, The University of Auckland, Auckland, New Zealand; Centre for Brain Research, School of Medical Sciences, FMHS, The University of Auckland, Auckland, New Zealand.
authors.forename: Janitha M
authors.initials: JM
authors.lastname: Mudannayake
authors.affiliation: Department of Pharmacology and Clinical Pharmacology, The University of Auckland, Auckland, New Zealand; Centre for Brain Research, School of Medical Sciences, FMHS, The University of Auckland, Auckland, New Zealand.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Mouravlev
authors.affiliation: Department of Pharmacology and Clinical Pharmacology, The University of Auckland, Auckland, New Zealand; Centre for Brain Research, School of Medical Sciences, FMHS, The University of Auckland, Auckland, New Zealand.
authors.forename: Dahna M
authors.initials: DM
authors.lastname: Fong
authors.affiliation: Department of Pharmacology and Clinical Pharmacology, The University of Auckland, Auckland, New Zealand; Centre for Brain Research, School of Medical Sciences, FMHS, The University of Auckland, Auckland, New Zealand.
authors.forename: Deborah
authors.initials: D
authors.lastname: Young