Background and aims Huntington’s Disease (HD) is a neurodegenerative condition caused by abnormal expansions (>37) of a polyglutamine (PolyQ) tract in the huntingtin protein (Htt). Dopamine (DA) induces oxidative stress and causes toxicity in neurons. DA may exacerbate neuronal loss in the striatum. Autophagy is a lysosomal degradation pathway known to clear protein aggregates. We hypothesised that DA could induce toxicity in Htt-expressing dopaminergic neurons by inhibiting the clearing activity of the autophagy system.
Methods Normal and mutant Htt were ectopically expressed in dopaminergic human neuroblastoma SH-SY5Y cells. The autophagic activity and Htt expression were studied by Western blotting and immunofluorescence. Apoptosis was assessed by FACS analysis, Propidium Iodide (PI) staining and Western blotting.
Results Hyper-expression of mutant Htt “per se” reduced cell proliferation and induced cell death. These effects were associated with impairment of the autophagy pathway. DA caused apoptotic and necrotic cell death in SH-SY5Y cells expressing the mutant Htt. In the latter cells, DA further reduced the formation of autophagosome, thus preventing the degradation of Htt aggregates. DA induced oxidative stress at mitochondrial level with generation of anion superoxide ROS.
Conclusions DA causes the death of neurons expressing the mutant Htt through the inhibition of the autophagy degradation pathway. We suggest that DA-induced mitochondrial oxidative stress promotes the generation of ROS that inhibit ATG4, the enzyme needed for the LC3 I to LC3 II conversion. Our data help explain why alterations in DA function conjugate to the inhibition of autophagy system may play a significant role in the motor and cognitive symptoms of HD.
Acknowledgements MIUR (PRIN contract #20109MXHMR_004, to MABM)
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.