title: Therapeutic potential of the endoplasmic reticulum located and secreted CDNF/MANF family of neurotrophic factors in Parkinson's disease.
abstract: Parkinson's disease (PD) is a progressive neurodegenerative disorder where dopamine (DA) neurons in the substantia nigra degenerate and die. Since no cure for PD exists, there is a need for disease-modifying drugs. Glial cell line-derived neurotrophic factor (GDNF) and related neurturin (NRTN) can protect and repair DA neurons in neurotoxin animal models of PD. However, GDNF was unable to rescue DA neurons in an α-synuclein model of PD, and both factors have shown modest effects in phase two clinical trials. Neurotrophic factors (NTFs), cerebral DA NTF (CDNF) and mesencephalic astrocyte-derived NTF (MANF) form a novel family of evolutionarily conserved, endoplasmic reticulum (ER) located and secreted NTFs. CDNF and MANF have a unique structure and an unparalleled dual mode of action that differs from other known NTFs. Both protect cells from ER stress, and regulate the unfolded protein response via interacting with chaperons, and CDNF dissolves intracellular α-synuclein aggregates. By binding to putative plasma membrane receptors, they promote the survival of DA neurons similarly to conventional NTFs. In animal models of PD, CDNF protects and repairs DA neurons, regulates ER stress, and improves motor function more efficiently than other NTFs.
authors.affiliation: Institute of Biotechnology, University of Helsinki, Finland.
authors.forename: Merja H
authors.initials: MH
authors.lastname: Voutilainen
authors.affiliation: Institute of Biotechnology, University of Helsinki, Finland; Department of Gene Technology, Tallinn University of Technology, Tallinn, Estonia.
authors.forename: Urmas
authors.initials: U
authors.lastname: Arumäe
authors.affiliation: Institute of Biotechnology, University of Helsinki, Finland.
authors.forename: Mikko
authors.initials: M
authors.lastname: Airavaara
authors.affiliation: Institute of Biotechnology, University of Helsinki, Finland. Electronic address: Mart.Saarma@helsinki.fi.
authors.forename: Mart
authors.initials: M
authors.lastname: Saarma
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology / Q000627:therapeutic use*; D059290:Dopaminergic Neurons / Q000502:physiology; D004721:Endoplasmic Reticulum / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress; D006801:Humans; D058990:Molecular Targeted Therapy; D009414:Nerve Growth Factors / Q000494:pharmacology / Q000502:physiology / Q000627:therapeutic use*; D010300:Parkinson Disease / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D000978:Antiparkinson Agents; C522217:CDNF protein, human; C099695:MANF protein, human; D009414:Nerve Growth Factors
keywords: Cerebral Dopamine neurotrophic factor; Dopamine; Mesencephalic astrocyte-derived neurotrophic factor; Neurotrophic factors; Parkinson’s disease; Regeneration