| First Author | Lewandowski NM | Year | 2010 |
| Journal | Proc Natl Acad Sci U S A | Volume | 107 |
| Issue | 39 | Pages | 16970-5 |
| PubMed ID | 20837543 | Mgi Jnum | J:164567 |
| Mgi Id | MGI:4834681 | Doi | 10.1073/pnas.1011751107 |
| Citation | Lewandowski NM, et al. (2010) Polyamine pathway contributes to the pathogenesis of Parkinson disease. Proc Natl Acad Sci U S A 107(39):16970-5 |
| abstractText | 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 alpha-synuclein toxicity, we investigated a yeast model expressing alpha-synuclein. Polyamines were found to enhance the toxicity of alpha-synuclein, and an unbiased genome-wide screen for modifiers of alpha-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 alpha-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. |
