Targeting bone morphogenetic protein signalling in midbrain dopaminergic neurons as a therapeutic approach in Parkinson's disease

Abstract

Parkinson's disease (PD) is the second most common neurodegenerative disease, characterized by the degeneration of midbrain dopaminergic (mDA) neurons and their axons, and aggregation of α-synuclein, which leads to motor and late-stage cognitive impairments. As the motor symptoms of PD are caused by the degeneration of a specific population of mDA neurons, PD lends itself to neurotrophic factor therapy. The goal of this therapy is to apply a neurotrophic factor that can slow down, halt or even reverse the progressive degeneration of mDA neurons. While the best known neurotrophic factors are members of the glial cell line-derived neurotrophic factor (GDNF) family, their lack of clinical efficacy to date means that it is important to continue to study other neurotrophic factors. Bone morphogenetic proteins (BMPs) are naturally secreted proteins that play critical roles during nervous system development and in the adult brain. In this review, we provide an overview of the BMP ligands, BMP receptors (BMPRs) and their intracellular signalling effectors, the Smad proteins. We review the available evidence that BMP-Smad signalling pathways play an endogenous role in mDA neuronal survival in vivo, before outlining how exogenous application of BMPs exerts potent effects on mDA neuron survival and axon growth in vitro and in vivo. We discuss the molecular mechanisms that mediate these effects, before highlighting the potential of targeting the downstream effectors of BMP-Smad signalling as a novel neuroprotective approach to slow or stop the degeneration of mDA neurons in PD.

Transcriptome Analysis Reveals Distinct Responses to Physiologic versus Toxic Manganese Exposure in Human Neuroblastoma Cells

“…All of these genes increased with Mn in a dose-dependent manner and belonged to multiple molecular functional categories highlighted in Figure 1A . Of these, three genes represent binding functional category (GO:0005488, GO:0046982) ( Figure 4A )— BMPR1A (bone morphogenetic protein receptor 1A), which encodes a protein with neurotrophic effects involved with transmitting chemical signals from the cell membrane to the nucleus and has been suggested as a therapeutic target in Parkinson’s disease (O’Keeffe et al, 2017); CYR61 (cysteine-rich angiogenic inducer 61), which encodes a matricellular protein which plays an important role in cell adhesion and migration, wherein CYR61 gene induction is necessary for neuronal cell death (Kim et al, 2003); and BIK (BCL2-interacting killer), apoptosis-inducing gene. Two genes represented the catalytic activity category (GO:0003824) ( Figure 4B )— IARS (isoleucyl-tRNA synthetase), involved in amino acid metabolism, and mutations in this gene have been associated with intellectual disability (Kopajtich et al, 2016), and OXSR1 (oxidative stress–responsive 1), which belongs to Ser/Thr protein kinase family which regulates downstream kinases in response to environmental stress and is overexpressed in schizophrenia (Arion and Lewis, 2011).…”

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

“…The effects of GDF5 on mDA neurons are dependent on BMPR1B and Smad signaling ( Hegarty et al., 2014 ; Hegarty et al, 2018 ), whereas the downstream changes that mediate the neurotrophic effects of GDF5 on mDA neurons are unknown. This is important because GDF5 has been proposed as a candidate neurotrophic factor for therapeutic application in PD ( O’Keeffe et al, 2017 ; Paul and Sullivan, 2018 ), where a characteristic feature is axonal degeneration ( Burke and O'Malley, 2013 ; O'Keeffe and Sullivan, 2018 ).…”

Ligand-receptor promiscuity enables cellular addressing

“…If these complications result from undesired activation of off-target cell types, using a combination of ligands could potentially provide more specific addressing of the appropriate cell type(s). Other potential therapeutic applications for modulators of BMP signaling include cardiac fibrosis, where BMP2 and BMP7 have both shown promise in animal models (Flevaris et al, 2017;Wang et al, 2012); Parkinson disease, where BMP2 and GDF5 both appear to promote survival of dopaminergic neurons (Hegarty et al, 2014;O'Keeffe et al, 2017;O'Sullivan et al, 2010); and cancer, where inhibition of BMP signaling reduces tumor formation in mice (Yokoyama et al, 2017). As the range of clinical applications targeting BMP signaling continues to grow, it will be essential to determine whether combinations of ligands could provide greater specificity than individual ligands.…”