The potential of bone morphogenetic protein 2 as a neurotrophic factor for Parkinson's disease

Abstract

Parkinson's disease is the second most common neurodegenerative disorder; it affects 1% of the population over the age of 65. The number of people with Parkinson's disease is set to rapidly increase due to changing demographics and there is an unmet clinical need for disease-modifying therapies. The pathological hallmarks of Parkinson's disease are the progressive degeneration of dopaminergic neurons in the substantia nigra and their axons which project to the striatum, and the aggregation of α-synuclein; these result in a range of debilitating motor and non-motor symptoms. The application of neurotrophic factors to protect and potentially regenerate the remaining dopaminergic neurons is a major area of research interest. However, this strategy has had limited success to date. Clinical trials of two well-known neurotrophic factors, glial cell line-derived neurotrophic factor and neurturin, have reported limited efficacy in Parkinson's disease patients, despite these factors showing potent neurotrophic actions in animal studies. There is therefore a need to identify other neurotrophic factors that can protect against α-synuclein-induced degeneration of dopaminergic neurons. The bone morphogenetic protein (BMP) family is the largest subgroup of the transforming growth factor-β superfamily of proteins. BMPs are naturally secreted proteins that play crucial roles throughout the developing nervous system. Importantly, many BMPs have been shown to be potent neurotrophic factors for dopaminergic neurons. Here we discuss recent work showing that transcripts for the BMP receptors and BMP2 are co-expressed with several key markers of dopaminergic neurons in the human substantia nigra, and evidence for downregulation of BMP2 expression at distinct stages of Parkinson's disease. We also discuss studies that explored the effects of BMP2 treatment, in in vitro and in vivo models of Parkinson's disease. These studies found potent effects of BMP2 on dopaminergic neurites, which is important given that axon degeneration is increasingly recognized as a key early event in Parkinson's disease. Thus, the aim of this mini-review is to give an overview of the BMP family and the BMP-Smad signalling pathway, in addition to reviewing the available evidence demonstrating the potential of BMP2 for Parkinson's disease therapy.

Keywords: BMP2; Parkinson’s disease; axon growth; dopaminergic neurons; neuroprotection; neuroregeneration; neurotrophic factor; α-synuclein.

Figure 1

Schematic of BMP-Smad signalling from cell membrane to nucleus. BMP ligands bind to a heterotetrameric complex of type I and type II serine/threonine kinase cell surface receptors, causing the constitutively active type II receptor to intracellularly phosphorylate the type I receptor. R-Smads and I-Smads compete for binding at the receptor complex for phosphorylation and subsequent complex formation with Co-Smad 4. This complex translocates to the nucleus, where it binds to the DNA and alters transcription. BMP: Bone morphogenetic protein. BMPR: BMP receptor; Co-Smad 4: common-mediator Smad 4; I-Smads: inhibitory Smads; R-Smads: receptor-regulated Smads.

Figure 2

rhBMP2 promotes neurite length in SH-SY5Y cells and in primary cultures of dopaminergic neurons. (A) SH-SY5Y cells and (B) TH⁺ dopaminergic neurons in primary cultures of E14 rat VM, after treatment with 50 ng/mL rhBMP2 for 72 hours compared to untreated controls. Scale bar: 50 µm. rhBMP2: Recombinant human bone morphogenetic protein 2; TH⁺: tyrosine hydroxylase-positive; VM: ventral mesencephalon.