title: Biochemical and morphological consequences of human α-synuclein expression in a mouse α-synuclein null background.
abstract: A consensus about the functions of human wild-type or mutated α-synuclein (αSYN) is lacking. Both forms of αSYN are implicated in Parkinson's disease, whereas the wild-type form is implicated in substance abuse. Interactions with other cellular proteins and organelles may meditate its functions. We developed a series of congenic mouse lines containing various allele doses or combinations of the human wild-type αSYN (hwαSYN) or a doubly mutated (A30P*A53T) αSYN (hm(2) αSYN) in a C57Bl/6J line spontaneously deleted in mouse αSYN (C57BL/6JOla). Both transgenes had a functional role in the nigrostriatal system, demonstrated by significant elevations in striatal catecholamines, metabolites and the enzyme tyrosine hydroxylase compared with null-mice without a transgene. Consequences occurred when the transgenes were expressed at a fraction of the endogenous level. Hemizygous congenic mice did not exhibit any change in the number or size of dopaminergic neurons in the ventral midbrain at 9 months of age. Human αSYN was predominantly located in neuronal cell bodies, neurites, synapses, and in intraneuronal/intraneuritic aggregates. The hm(2) αSYN transgene resulted in more aggregates and dystrophic neurites than did the hw5 transgene. The hwαSYN transgene resulted in higher expression of two striatal proteins, synaptogamin 7 and UCHL1, compared with the levels of the hm(2) αSYN transgene. These observations suggest that mutations in αSYN may impair specific functional domains, leaving others intact. These lines may be useful for exploring interactions between hαSYN and environmental or genetic risk factors in dopamine-related disorders using a mouse model.
authors.affiliation: Department of Pathology and Lab Medicine, Robert Wood Johnson Medical School (RWJMS), Piscataway, NJ 08854, USA.
authors.forename: Kavita
authors.initials: K
authors.lastname: Prasad
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Tarasewicz
authors.forename: Pamela A Ohman
authors.initials: PA
authors.lastname: Strickland
authors.forename: Michael
authors.initials: M
authors.lastname: O'Neill
authors.forename: Stephen N
authors.initials: SN
authors.lastname: Mitchell
authors.forename: Kalpana
authors.initials: K
authors.lastname: Merchant
authors.forename: Samnang
authors.initials: S
authors.lastname: Tep
authors.forename: Kathryn
authors.initials: K
authors.lastname: Hilton
authors.forename: Akash
authors.initials: A
authors.lastname: Datwani
authors.forename: Manuel
authors.initials: M
authors.lastname: Buttini
authors.forename: Sarah
authors.initials: S
authors.lastname: Mueller-Steiner
authors.forename: Eric K
authors.initials: EK
authors.lastname: Richfield
mesh_terms: D000818:Animals; D002395:Catecholamines / Q000032:analysis; D002851:Chromatography, High Pressure Liquid; D003342:Corpus Striatum / Q000737:chemistry / Q000166:cytology / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D019966:Substance-Related Disorders / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D013569:Synapses / Q000378:metabolism / Q000648:ultrastructure; D019076:Transgenes; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: D002395:Catecholamines; D051844:alpha-Synuclein