GDNF family receptor complexes are emerging drug targets

Bespalov, Maxim M.; Saarma, Märt

doi:10.1016/j.tips.2006.12.005

Cited by 159 publications

(122 citation statements)

References 28 publications

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“…Neurturin expression by CERE-120 was detected in the targeted putamen, but no evidence was provided for the retrograde axonal transport of NRTN to the dopaminergic cell bodies in the SN, evidently reducing bioactivity of the factor. Diffusion of GDNF and NRTN are known to be limited in brain tissue due to the binding to the heparan sulfate proteoglycans (Bespalov and Saarma, 2007).…”

Section: Potential Therapeutic Proteinsmentioning

confidence: 99%

“…Traditionally, there are three families of NTFs: Neurotrophins NGF, BDNF, neurotrophin-3 (NT-3) and NT-4 (Huang and Reichardt, 2001;Lu et al, 2005); glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) GDNF, neurturin (NRTN), artemin (ARTN), and persephin (PSPN) (Airaksinen and Saarma, 2002;Bespalov and Saarma, 2007); and neuropoietic cytokines (also referred as interleukin-6 (IL-6) family) (Heinrich et al, 2003;Bauer et al, 2007). Members of these families either signal through transmembrane receptor tyrosine kinases or via kinases that interact with their receptors (Bespalov and Saarma, 2007). Neurotrophic activities are also shown by other trophic and growth factors, e.g., members of transforming growth factor b, vascular endothelial growth factor (VEGF), insulin-like growth factor, and fibroblast growth factor (FGF) families (Grothe and Timmer, 2007;Zacchigna et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

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Novel CDNF/MANF family of neurotrophic factors

Lindholm

Saarma

2010

Developmental Neurobiology

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Current therapeutic interventions for neurodegenerative diseases alleviate only disease symptoms, while treatments that could stop or reverse actual degenerative processes are not available. Parkinson's disease (PD) is a movement disorder with characteristic degeneration of dopaminergic neurons in the midbrain. Few neurotrophic factors (NTFs) that promote survival, maintenance, and differentiation of affected brain neurons are considered as potential therapeutic agents for the treatment of neurodegenerative diseases. Thus, it is important to search and study new NTFs that could also be used in therapy. In this review, we discuss novel evolutionary conserved family of NTFs consisting of two members in the vertebrates, cerebral dopamine neurotrophic factor (CDNF) and mesencephalic astrocyte-derived neurotrophic factor (MANF). Invertebrates, including Drosophila and Caenorhabditis have a single protein homologous to vertebrate CDNF/ MANF. Characteristic feature of these proteins is eight structurally conserved cysteine residues, which determine the protein fold. The crystal structure analysis revealed that CDNF and MANF consist of two domains; an amino-terminal saposin-like domain that may interact with lipids or membranes, and a presumably unfolded carboxy-terminal domain that may protect cells against endoplasmic reticulum stress. CDNF and MANF protect midbrain dopaminergic neurons and restore motor function in 6-hydroxydopamine rat model of PD in vivo. In line, Drosophila MANF is needed for the maintenance of dopaminergic neurites and dopamine levels in the fly, suggesting that the function of CDNF/MANF proteins is evolutionary conserved. Future studies will reveal the receptors and mode of action of these novel factors, which are potential therapeutic proteins for the treatment of PD. ' 2010 Wiley Periodicals, Inc. Develop Neurobiol 70: 360-371, 2010

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Section: Potential Therapeutic Proteinsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Novel CDNF/MANF family of neurotrophic factors

Lindholm

Saarma

2010

Developmental Neurobiology

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165

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“…The four members of the GDNF family have different receptors (GFR␣ types 1-4) but the specificity for the receptors is not exclusive; for example, neurturin can act through the GDNF receptor GFR␣1, as well as through GFR␣2. 8 A new family of trophic factors with particular relevance to PD has been identified. This family currently has two members: mesencephalic astrocyte-derived neurotrophic factor (MANF) and conserved dopamine neurotrophic factor (CDNF).…”

Section: Trophic Factors In the Central Nervous Systemmentioning

confidence: 99%

“…71 Small molecules that cross the BBB and directly stim-ulate receptors or transduction mechanisms of trophic factors suggest an alluring strategy to generate trophic actions in the CNS. 8 For example, a small, nonpeptide quinol can activate the GDNF receptor-RET complex. 72 High-throughput screening techniques could be used to search for candidate drugs that act by this mechanism.…”

Section: Manipulating Trophic Factors For Therapeutic Benefitmentioning

confidence: 99%

“…Because Amgen held the patent on GDNF, Ceregene (San Diego, CA) has used NRTN (neurturin), another member of the GDNF-like family of trophic factor signaling through the same receptor family and RET activation. 8 Neurturin has been demonstrated to be neuroprotective in a number of animal models of parkinsonism. The evidence that it is neurorestorative is more limited.…”

Section: Gene Therapy With Neurturinmentioning

confidence: 99%

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Treatment of Parkinson’s Disease with Trophic Factors

2008

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Summary: Trophic factors are proteins that support and protect subpopulations of cells. A number have been reported to act on dopaminergic neurons in vitro and in vivo, making them potential therapeutic candidates for Parkinson's disease. All of these candidate factors protect dopaminergic neurons if given prior to, or with, selective neurotoxins. Fewer trophic factors, primarily glial-derived neurotrophic factor (GDNF) and its relative, neurturin (NRTN; also known as NTN), have been shown to restore function in damaged dopamine neurons after the acute effects of neurotoxins have subsided. A major barrier to clinical translation has been delivery. GDNF delivered by intracerebroventricular injection in patients was ineffective, probably because GDNF did not reach the target, the putamen, and intraputaminal infusion was ineffective, probably because of limited distribution within the putamen. A randomized clinical trial with gene therapy for NRTN is underway, in an attempt to overcome these problems with targeting and distribution. Other strategies are available to induce trophic effects in the CNS, but have not yet been the focus of human research. To date, clinical trials have focused on restoration of function (i.e., improvement of parkinsonism). Protection (i.e., slowing or halting disease progression and functional decline) might be a more robust effect of trophic agents. Laboratory research points to their effectiveness in protecting neurons and even restoring dopaminergic function after a monophasic neurotoxic insult. Utility for such compounds in patients with Parkinson's disease and ongoing loss of dopaminergic neurons remains to be proven.

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