MANF, ER STRESS AND THE PATHOPHYSIOLOGY OF PARKINSON’S DISEASE

Abstract

Nearly 10 million people worldwide live with Parkinson’s Disease (PD), a disease marked by the degeneration of midbrain dopaminergic neurons. Current treatments are symptomatic and can incur undesirable side effects. The recently discovered neurotrophic factor (NTF), known as mesencephalic astrocyte-derived neurotrophic factor (MANF), has proven to be an interesting candidate to study within the context of PD because this NTF is involved in endoplasmic reticulum (ER) homeostasis and the unfolded protein response (UPR), both of which are abnormal in PD. MANF is an evolutionary conserved NTF identified in both invertebrate and vertebrate species that is mainly localized within the ER and has demonstrated to be neuroprotective against midbrain DA neuron degeneration in vitro. Intracellular MANF helps stop the unfolded protein response (UPR) during ER stress and therefore prevents the cell from going into apoptosis. Lentiviral mediated shRNA knockdown of MANF in rats has led to the manifestation of PD like symptoms and motor deficits mainly due to the death of dopaminergic neurons in the substantia nigra (SN). mRNA analysis of the ER stress marker glucose-regulated protein 78 (GRP78) and the transcription factor C/EBP homologous protein (CHOP) have shown increased levels apoptosis following MANF knockdown. Furthermore, the phytochemical curcumin is a spice that has been widely acknowledged for its anti-oxidant and anti-apoptotic properties and in-vitro investigation of its protective role has revealed that curcumin prevents 6-hyrodroxydopamine induced cytotoxicity and that it upregulates MANF expression and therefore employs MANF during its protective cascade. These findings, therefore, acknowledge MANF’s significance as a neuroprotective agent and hence points to its future development as a potential agent against neurodegenerative disorders.