title: Unconventional neurotrophic factors CDNF and MANF: Structure, physiological functions and therapeutic potential.
abstract: Cerebral dopamine neurotrophic factor (CDNF) and mesencephalic astrocyte-derived neurotrophic factor (MANF) promote the survival of midbrain dopaminergic neurons which degenerate in Parkinson's disease (PD). However, CDNF and MANF are structurally and functionally clearly distinct from the classical, target-derived neurotrophic factors (NTFs) that are solely secreted proteins. In cells, CDNF and MANF localize in the endoplasmic reticulum (ER) and evidence suggests that MANF, and possibly CDNF, is important for the maintenance of ER homeostasis. MANF expression is particularly high in secretory tissues with extensive protein production and thus a high ER protein folding load. Deletion of MANF in mice results in a diabetic phenotype and the activation of unfolded protein response (UPR) in the pancreatic islets. However, information about the intracellular and extracellular mechanisms of MANF and CDNF action is still limited. Here we will discuss the structural motifs and physiological functions of CDNF and MANF as well as their therapeutic potential for the treatment of neurodegenerative diseases and diabetes. Currently available knockout models of MANF and CDNF in mice, zebrafish and fruit fly will increase information about the biology of these interesting proteins.
authors.affiliation: Institute of Biotechnology, P.O.Box 56, Viikinkaari 5, FI-00014, University of Helsinki, Finland.
authors.forename: Maria
authors.initials: M
authors.lastname: Lindahl
authors.affiliation: Institute of Biotechnology, P.O.Box 56, Viikinkaari 5, FI-00014, University of Helsinki, Finland.
authors.forename: Mart
authors.initials: M
authors.lastname: Saarma
authors.affiliation: Institute of Biotechnology, P.O.Box 56, Viikinkaari 5, FI-00014, University of Helsinki, Finland. Electronic address: paivi.pulkkila@helsinki.fi.
authors.forename: Päivi
authors.initials: P
authors.lastname: Lindholm
mesh_terms: D000818:Animals; D003920:Diabetes Mellitus / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D009414:Nerve Growth Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use*; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000378:metabolism; D018696:Neuroprotective Agents / Q000737:chemistry / Q000627:therapeutic use
chemical_list: D009414:Nerve Growth Factors; D018696:Neuroprotective Agents
keywords: CDNF; Diabetes; ER stress; MANF; Parkinson's disease