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Summary Loss of midbrain dopaminergic (mDA) neurons and their axons is central to Parkinson's disease (PD). Growth differentiation factor (GDF)5 is a potential neurotrophic factor for PD therapy. However, the molecular mediators of its neurotrophic action are unknown. Our proteomics analysis shows that GDF5 increases the expression of serine threonine receptor-associated protein kinase (STRAP) and nucleoside diphosphate kinase (NME)1 in the SH-SY5Y neuronal cell line. GDF5 overexpression increased NME1 expression in adult rat brain in vivo . NME and STRAP mRNAs are expressed in developing and adult rodent midbrain. Expression of both STRAP and NME1 is necessary and sufficient for the promotion of neurite growth in SH-SY5Y cells by GDF5. NME1 treatment increased neurite growth in both SH-SY5Y cells and cultured mDA neurons. Expression patterns of NME and STRAP are altered in PD midbrain. NME1 and STRAP are thus key mediators of GDF5's neurotrophic effects, rationalizing their future study as therapeutic targets for PD.

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