STRAP and NME1 Mediate the Neurite Growth-Promoting Effects of the Neurotrophic Factor GDF5

Jayanth Anantha,Aideen Sullivan,Sean Wyatt,Gerard O'Keeffe

doi:10.2139/ssrn.3571299

Abstract

The loss of midbrain dopaminergic (mDA) neurons and their axons is central to Parkinson’s disease (PD). Growth differentiation factor (GDF)5 has been proposed as a neurotrophic factor for PD therapy. However the molecular mediators of its neurotrophic action are unknown. To address this, we performed proteomics analysis and identified that GDF5 increases the expression of two proteins, serine threonine receptor associated protein kinase (STRAP) and nucleoside diphosphate kinase (NME)1, in the SH-SY5Y neuronal cell line. We show that mRNAs encoding these proteins are expressed in the developing and adult midbrain in vivo. We also report that the expression of both STRAP and NME1 is necessary and sufficient for the promotion of neurite growth by GDF5 on SH-SY5Y cells. In summary, we identify NME1 and STRAP as key mediators of the neurotrophic effects of GDF5, which rationalises their further study as therapeutic targets for the protection of dopaminergic neurons in PD.

Highlights

Parkinson’s disease (PD) is the second most common neurodegenerative disorder, affecting 1% of the population older than 60 years (Lees et al, 2009; Tysnes and Storstein, 2017)
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
SH-SY5Y cells were plated for 24 h before they were treated with 100 ng/mL recombinant human GDF5 for 30, 60, or 120 min

Summary

Introduction

Parkinson’s disease (PD) is the second most common neurodegenerative disorder, affecting 1% of the population older than 60 years (Lees et al, 2009; Tysnes and Storstein, 2017). Despite promising results in open-label clinical trials (Gill et al, 2003; Slevin et al, 2007; Marks et al, 2008), subsequent randomized double-blind trials of the dopaminergic neurotrophic factors, glial cell line-derived neurotrophic factor (GDNF) and neurturin, failed to meet their primary endpoints (Lang et al, 2006; Marks et al, 2010; Warren Olanow et al, 2015; Whone et al, 2019) This has been suggested to be due to the downregulation of Ret, the common co-receptor for GDNF and neurturin, by alpha-synuclein (Decressac et al, 2012), a protein that is present in aggregates, called Lewy bodies, in the PD brain. It is important to characterize the effects of other factors that have neurotrophic effects on mDA neurons, and to decipher the molecular mechanisms that underlie their beneficial effects on this neuronal population

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