Growth differentiation factor 5: a neurotrophic factor with neuroprotective potential in Parkinson's disease

Abstract

Parkinson's disease is the most common movement disorder worldwide, affecting over 6 million people. It is an age-related disease, occurring in 1% of people over the age of 60, and 3% of the population over 80 years. The disease is characterized by the progressive loss of midbrain dopaminergic neurons from the substantia nigra, and their axons, which innervate the striatum, resulting in the characteristic motor and non-motor symptoms of Parkinson's disease. This is paralleled by the intracellular accumulation of α-synuclein in several regions of the nervous system. Current therapies are solely symptomatic and do not stop or slow disease progression. One promising disease-modifying strategy to arrest the loss of dopaminergic neurons is the targeted delivery of neurotrophic factors to the substantia nigra or striatum, to protect the remaining dopaminergic neurons of the nigrostriatal pathway. However, clinical trials of two well-established neurotrophic factors, glial cell line-derived neurotrophic factor and neurturin, have failed to meet their primary end-points. This failure is thought to be at least partly due to the downregulation by α-synuclein of Ret, the common co-receptor of glial cell line-derived neurorophic factor and neurturin. Growth/differentiation factor 5 is a member of the bone morphogenetic protein family of neurotrophic factors, that signals through the Ret-independent canonical Smad signaling pathway. Here, we review the evidence for the neurotrophic potential of growth/differentiation factor 5 in in vitro and in vivo models of Parkinson's disease. We discuss new work on growth/differentiation factor 5's mechanisms of action, as well as data showing that viral delivery of growth/differentiation factor 5 to the substantia nigra is neuroprotective in the α-synuclein rat model of Parkinson's disease. These data highlight the potential for growth/differentiation factor 5 as a disease-modifying therapy for Parkinson's disease.

Keywords: Parkinson’s disease; Smad signaling; adeno-associated virus; bone morphogenetic protein; dopaminergic neurons; growth/differentiation factor 5; neurodegeneration; neuroprotection; neurotrophic factor; α-synuclein.

Figure 1

Growth/differentiation factor 5 (GDF5) signals via the canonical Smad signaling pathway. ① GDF5 ligands preferentially bind to BMP receptor (BMPR)1B or BMPR2 transmembrane receptors. ② Upon ligand binding, receptor-regulated Smads (R-Smads) become phosphorylated and form a complex with the common mediator Smad 4 (Co-Smad 4). ③ This complex translocates to the nucleus where it binds to the DNA and ④ alters transcription, including the upregulation of transcripts for NME1 and STRAP. Figure created using https://smart.servier.com/. Creative commons by 3.0.

Figure 2

Viral overexpression of growth/differentiation factor 5 (GDF5) in the substantia nigra protects dopaminergic neurons and their striatal terminals against α-synuclein-induced degeneration. (A) Schema showing the experimental design in which an adeno-associated virus-Control (AAV-Cont) or an AAV-α-synuclein (AAV-αSyn) vector, together with either an AAV-Cont or AAV-GDF5 vector, was administered by stereotactic injection into the substantia nigra of adult rats on day 0, before nigrostriatal integrity was examined 20 weeks later. (B, C) Images of tyrosine hydroxylase (TH) immunostaining at 20 weeks showing the integrity of (B) TH-positive fibers in the striatum and (C) TH-positive neurons in the substantia nigra. Scale bar: 1 mm. Reprinted from Goulding et al. (2020a).