title: Polyamine pathway contributes to the pathogenesis of Parkinson disease.
abstract: The full complement of molecular pathways contributing to the pathogenesis of Parkinson disease (PD) remains unknown. Here we address this issue by taking a broad approach, beginning by using functional MRI to identify brainstem regions differentially affected and resistant to the disease. Relying on these imaging findings, we then profiled gene expression levels from postmortem brainstem regions, identifying a disease-related decrease in the expression of the catabolic polyamine enzyme spermidine/spermine N1-acetyltransferase 1 (SAT1). Next, a range of studies were completed to support the pathogenicity of this finding. First, to test for a causal link between polyamines and α-synuclein toxicity, we investigated a yeast model expressing α-synuclein. Polyamines were found to enhance the toxicity of α-synuclein, and an unbiased genome-wide screen for modifiers of α-synuclein toxicity identified Tpo4, a member of a family of proteins responsible for polyamine transport. Second, to test for a causal link between SAT1 activity and PD histopathology, we investigated a mouse model expressing α-synuclein. DENSPM (N1, N11-diethylnorspermine), a polyamine analog that increases SAT1 activity, was found to reduce PD histopathology, whereas Berenil (diminazene aceturate), a pharmacological agent that reduces SAT1 activity, worsened the histopathology. Third, to test for a genetic link, we sequenced the SAT1 gene and a rare but unique disease-associated variant was identified. Taken together, the findings from human patients, yeast, and a mouse model implicate the polyamine pathway in PD pathogenesis.
authors.affiliation: Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Lewandowski
authors.forename: Shulin
authors.initials: S
authors.lastname: Ju
authors.forename: Miguel
authors.initials: M
authors.lastname: Verbitsky
authors.forename: Barbara
authors.initials: B
authors.lastname: Ross
authors.forename: Melissa L
authors.initials: ML
authors.lastname: Geddie
authors.forename: Edward
authors.initials: E
authors.lastname: Rockenstein
authors.forename: Anthony
authors.initials: A
authors.lastname: Adame
authors.forename: Alim
authors.initials: A
authors.lastname: Muhammad
authors.forename: Jean Paul
authors.initials: JP
authors.lastname: Vonsattel
authors.forename: Dagmar
authors.initials: D
authors.lastname: Ringe
authors.forename: Lucien
authors.initials: L
authors.lastname: Cote
authors.forename: Susan
authors.initials: S
authors.lastname: Lindquist
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Petsko
authors.forename: Karen
authors.initials: K
authors.lastname: Marder
authors.forename: Lorraine N
authors.initials: LN
authors.lastname: Clark
authors.forename: Scott A
authors.initials: SA
authors.lastname: Small
mesh_terms: D000123:Acetyltransferases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001933:Brain Stem / Q000378:metabolism* / Q000473:pathology; D004133:Diminazene / Q000031:analogs & derivatives / Q000494:pharmacology; D014644:Genetic Variation; D006801:Humans; D008279:Magnetic Resonance Imaging; D051379:Mice; D008822:Mice, Transgenic; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010389:Pemoline / Q000031:analogs & derivatives / Q000494:pharmacology; D011073:Polyamines / Q000378:metabolism*; D051844:alpha-Synuclein / Q000378:metabolism*; D000099228:Diamine N-Acetyltransferase
chemical_list: D000123:Acetyltransferases; D004133:Diminazene; D010389:Pemoline; D011073:Polyamines; D051844:alpha-Synuclein; D000099228:Diamine N-Acetyltransferase; C049645:2-diethylamino-5-phenyl-2-oxazolin-4-one; C003915:diminazene aceturate