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

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 ofα-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 againstα-synuclein-induced degeneration of dopaminergic neurons.The bone morphogenetic protein(BMP)family is the largest subgroup of the transforming growth factor-βsuperfamily 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.

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

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 ofα-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 byα-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 theα-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.