Polyamine pathway contributes to the pathogenesis of Parkinson disease.

TitlePolyamine pathway contributes to the pathogenesis of Parkinson disease.
Publication TypeJournal Article
Year of Publication2010
AuthorsLewandowski NM, Ju S, Verbitsky M, Ross B, Geddie ML, Rockenstein E, Adame A, Muhammad A, Vonsattel JPaul, Ringe D, Cote L, Lindquist S, Masliah E, Petsko GA, Marder K, Clark LN, Small SA
JournalProc Natl Acad Sci U S A
Date Published2010 Sep 28
KeywordsAcetyltransferases, alpha-Synuclein, Animals, Brain Stem, Diminazene, Genetic Variation, Humans, Magnetic Resonance Imaging, Mice, Mice, Transgenic, Parkinson Disease, Pemoline, Polyamines

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.

Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID20837543
PubMed Central IDPMC2947879
Grant ListAG022074 / AG / NIA NIH HHS / United States
AG18440 / AG / NIA NIH HHS / United States
NS038372 / NS / NINDS NIH HHS / United States
NS36630 / NS / NINDS NIH HHS / United States
UL1 RR024156 / RR / NCRR NIH HHS / United States