α-Synuclein is implicated both in physiological functions at neuronal synaptic terminals as well as in pathological processes in the context of Parkinson's disease. However, the molecular mechanisms ...for these apparently diverse roles are unclear. Here we show that specific RNA transcript isoforms of α-synuclein with an extended 3' untranslated region, termed aSynL, appear selectively linked to pathological processes, relative to shorter α-synuclein transcripts. Common variants in the aSynL 3' untranslated region associated with Parkinson's disease risk promote the accumulation and translation of aSynL transcripts. The presence of intracellular dopamine can further enhance the relative abundance of aSynL transcripts through alternative polyadenylation site selection. We demonstrate that the presence of the extended aSynL transcript 3' untranslated region impacts accumulation of α-synuclein protein, which appears redirected away from synaptic terminals and towards mitochondria, reminiscent of Parkinson's disease pathology. Taken together, these findings identify a novel mechanism for aSyn regulation in the context of Parkinson's disease-associated genetic and environmental variations.
Background and purpose:
Activation of poly(ADP‐ribose) polymerase (PARP) is deleterious during cerebral ischemia. We assessed the influence of PARP activation induced by cerebral ischemia on the ...synthesis of proinflammatory mediators including the cytokines, tumour necrosis factor‐α (TNF‐α) and interleukin‐6 (IL‐6) and the adhesion molecules, E‐selectin and intercellular adhesion molecule‐1 (ICAM‐1).
Experimental approach:
Ischemia was induced by intravascular occlusion of the left middle cerebral artery for 1 h in male Swiss mice anaesthetized with ketamine and xylazine. The PARP inhibitor PJ34 (1.25–25 mg kg−1) was administered intraperitoneally 15 min before and 4 hours after, the onset of ischemia. Animals were killed 6 h or 24 h after ischemia and cerebral tissue removed for analysis.
Key results:
Ischemia increased TNF‐α protein in cerebral tissue at 6 and 24 h after ischemia. All doses of PJ34 blocked the increase in TNF‐α at 6 h and 25 mg kg−1 PJ34 had a sustained effect for up to 24 h. Quantitative real time polymerase chain reaction showed that PJ34 (25 mg kg−1) reduced the increase in TNF‐α mRNA by 70% at 6 h. PJ34 also prevented the increase in mRNAs encoding IL‐6 (−41%), E‐selectin (−81%) and ICAM‐1 (−54%). PJ34 (25 mg kg−1) reduced the infarct volume (−26%) and improved neurological deficit, 24 h after ischemia.
Conclusions and Implications:
PJ34 inhibited the increase in the mRNAs of four inflammatory mediators, caused by cerebral ischemia. The contribution of this effect of PJ34 to neuroprotection remains to be clarified.
British Journal of Pharmacology (2006) 149, 23–30. doi:10.1038/sj.bjp.0706837
α-Synuclein (aSyn) is implicated both in physiological functions at neuronal synaptic terminals as well as pathological processes in the context of Parkinson’s disease (PD). However, the molecular ...mechanisms for these apparently diverse roles are unclear. Here we show that specific RNA transcript isoforms of aSyn with an extended 3′UTR, aSynL, appear selectively linked to pathological processes, relative to shorter aSyn transcripts. Common variants in the aSynL 3′UTR associated with PD risk promote the accumulation and translation of aSynL transcripts. The presence of intracellular dopamine can further enhance the relative abundance of aSynL transcripts through alternative polyadenylation (PolyA) site selection. We demonstrate that presence of the extended aSynL transcript 3′UTR impacts accumulation of aSyn protein, which appears redirected away from synaptic terminals and towards mitochondria, reminiscent of PD pathology. Taken together, these findings identify a novel mechanism for aSyn regulation in the context of PD-associated genetic and environmental variation.
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