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Cre‐dependent AAV vectors for highly targeted expression of disease‐related proteins and neurodegeneration in the substantia nigra
Author(s) -
Grames Mychal S.,
Dayton Robert D.,
Jackson Kasey L.,
Richard Adam D.,
Lu Xiaohong,
Klein Ronald L.
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201701529rr
Subject(s) - substantia nigra , neurodegeneration , pars compacta , biology , adeno associated virus , transgene , neuroscience , parkinson's disease , alpha synuclein , microbiology and biotechnology , dopaminergic , vector (molecular biology) , genetics , pathology , dopamine , medicine , recombinant dna , disease , gene
Recombinant adeno‐associated virus (AAV) vectors are a popular genetic approach in neuroscience because they confer such efficient transgene expression in the brain and spinal cord. A number of studies have used AAV to express pathological disease‐related proteins in the dopaminergic neurons of the substantia nigra in situ (e.g ., a‐synuclein to model aspects of Parkinson's disease). The neuropathology and neurodegeneration of Parkinson's disease occur in a circumscribed pattern in the brain, and one of the most important goals of any gene transfer study is accurate, pinpoint targeting. By combining Cre recombinase‐dependent AAVs in Cre‐driver rats in which Cre is expressed only in the tyrosine hydroxylase neurons, we have achieved more highly targeted expression of several disease‐relevant neuropathological proteins in the substantia nigra pars compacta than using constitutive expression AAV vectors. Alpha‐synuclein, tau, transactive response DNA‐binding protein of 43 kDa, or the control fluorescent protein yellow fluorescent protein was individually expressed to induce highly targeted, dopaminergic neuron‐specific neurodegeneration models. The refined targeting foreshadows a next‐generation disease modeling system for expressing neurodegenerative disease‐related proteins in a disease‐relevant manner. We foresee specific utilities of this in vivo AAV vector targeting of pathological proteins to a well‐defined and well‐demarcated cell population.—Grames, M. S., Dayton, R. D., Jackson, K. L., Richard, A. D., Lu, X., Klein, R. L. Cre‐dependent AAV vectors for highly targeted expression of disease‐related proteins and neurodegeneration in the substantia nigra. FASEB J . 32, 4420‐4427 (2018). www.fasebj.org