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FEBS Lett. 2015 Dec 21;589(24 Pt A):3739-48. doi: 10.1016/j.febslet.2015.09.031. Epub 2015 Oct 9.

Therapeutic potential of the endoplasmic reticulum located and secreted CDNF/MANF family of neurotrophic factors in Parkinson's disease.

Author information

1
Institute of Biotechnology, University of Helsinki, Finland.
2
Institute of Biotechnology, University of Helsinki, Finland; Department of Gene Technology, Tallinn University of Technology, Tallinn, Estonia.
3
Institute of Biotechnology, University of Helsinki, Finland. Electronic address: Mart.Saarma@helsinki.fi.

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.

KEYWORDS:

Cerebral Dopamine neurotrophic factor; Dopamine; Mesencephalic astrocyte-derived neurotrophic factor; Neurotrophic factors; Parkinson’s disease; Regeneration

PMID:
26450777
DOI:
10.1016/j.febslet.2015.09.031
[Indexed for MEDLINE]
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