Polyamine pathway contributes to the pathogenesis of Parkinson disease.
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.
Lewandowski
Nicole M
NM
Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
Ju
Shulin
S
Verbitsky
Miguel
M
Ross
Barbara
B
Geddie
Melissa L
ML
Rockenstein
Edward
E
Adame
Anthony
A
Muhammad
Alim
A
Vonsattel
Jean Paul
JP
Ringe
Dagmar
D
Cote
Lucien
L
Lindquist
Susan
S
Masliah
Eliezer
E
Petsko
Gregory A
GA
Marder
Karen
K
Clark
Lorraine N
LN
Small
Scott A
SA
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
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