Evidence for an Additive Neurorestorative Effect of Simultaneously Administered CDNF and GDNF in Hemiparkinsonian Rats: Implications for Different Mechanism of Action

Voutilainen, Merja H.; Lorenzo, Francesca De; Stepanova, Polina; Bäck, Susanne; Yu, Li-Ying; Lindholm, Päivi; Pörsti, Eeva; Saarma, Märt; Männistö, Pekka T.; Tuominen, Raimo K.

doi:10.1523/eneuro.0117-16.2017

Cited by 45 publications

(40 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Another interesting finding is that there is likely a reciprocal regulation between p58 IPK and MANF in retinal cells undergoing ER stress. Recent studies show that MANF protects CNS neurons (Voutilainen et al, 2017 ) and markedly improves RGC survival in a rat glaucoma model (Gao et al, 2017 ). Our data support these findings and demonstrate that MANF inhibits ER stress-induced cell death and caspase-3 activation in retinal cells and explants.…”

Section: Discussionmentioning

confidence: 99%

p58IPK Is an Endogenous Neuroprotectant for Retinal Ganglion Cells

McLaughlin

Dhimal

et al. 2018

Front. Aging Neurosci.

View full text Add to dashboard Cite

p58IPK is an endoplasmic reticulum (ER)-resident chaperone playing a critical role in facilitating protein folding and protein homeostasis. Previously, we have demonstrated that p58IPK is expressed broadly in retinal neurons including retinal ganglion cells (RGCs) and loss of p58IPK results in age-related RGC degeneration. In the present study, we investigate the role of p58IPK in neuroprotection by in vitro and in vivo studies using primary RGC culture and two well-established disease-relevant RGC injury models: retinal ischemia/reperfusion (I/R) and microbead-induced ocular hypertension. Our results demonstrate that in both in vivo models, p58IPK −/− mice exhibit significantly increased RGC loss compared to wild type (WT) mice. In vitro, p58IPK-deficient RGCs show reduced viability and are more susceptible to cell death induced by the ER stress inducer tunicamycin (TM). Overexpression of p58IPK by adeno-associated virus (AAV) significantly diminishes TM-induced cell death in both WT and p58IPK −/− RGCs. Interestingly, we find that loss of p58IPK leads to reduced mRNA expression, but not the protein level, of mesencephalic astrocyte-derived neurotrophic factor (MANF), a neurotrophic factor that resides in the ER. Treatment with recombinant MANF protein protects R28 retinal neural cells and mouse retinal explants from TM-induced cell death. Taken together, our study suggests that p58IPK functions as an endogenous neuroprotectant for RGCs. The mechanisms underlying p58IPK’s neuroprotective action and the potential interactions between p58IPK and MANF warrant future investigation.

show abstract

Section: Discussionmentioning

confidence: 99%

p58IPK Is an Endogenous Neuroprotectant for Retinal Ganglion Cells

McLaughlin

Dhimal

et al. 2018

Front. Aging Neurosci.

View full text Add to dashboard Cite

show abstract

“…The advantages of the unilateral striatal 6‐OHDA model, however, are that it replicates the degeneration of the nigrostriatal tract and this effect is quite reproducible and well‐tolerated by the animals (Penttinen et al., ). The effects on locomotion can also be quantified reliably so it is very useful in screening for new therapeutics aimed at restoring or protecting the mesencephalic dopamine system (Penttinen, Parkkinen, Voutilainen, et al., ; Voutilainen et al., ). Behavioral assessment is much easier with regards to locomotor activity and the use of the contralateral side as a control enables reliable and physiologically relevant comparison in biochemical assessment of the lesion (Ungerstedt & Arbuthnott, ).…”

Section: Neurotoxin‐induced Modelsmentioning

confidence: 99%

Back and to the Future: From Neurotoxin‐Induced to Human Parkinson's Disease Models

et al. 2020

View full text Add to dashboard Cite

Parkinson's disease (PD) is an age‐related neurodegenerative disorder characterized by motor symptoms such as tremor, slowness of movement, rigidity, and postural instability, as well as non‐motor features like sleep disturbances, loss of ability to smell, depression, constipation, and pain. Motor symptoms are caused by depletion of dopamine in the striatum due to the progressive loss of dopamine neurons in the substantia nigra pars compacta. Approximately 10% of PD cases are familial arising from genetic mutations in α‐synuclein, LRRK2, DJ‐1, PINK1, parkin, and several other proteins. The majority of PD cases are, however, idiopathic, i.e., having no clear etiology. PD is characterized by progressive accumulation of insoluble inclusions, known as Lewy bodies, mostly composed of α‐synuclein and membrane components. The cause of PD is currently attributed to cellular proteostasis deregulation and mitochondrial dysfunction, which are likely interdependent. In addition, neuroinflammation is present in brains of PD patients, but whether it is the cause or consequence of neurodegeneration remains to be studied. Rodents do not develop PD or PD‐like motor symptoms spontaneously; however, neurotoxins, genetic mutations, viral vector‐mediated transgene expression and, recently, injections of misfolded α‐synuclein have been successfully utilized to model certain aspects of the disease. Here, we critically review the advantages and drawbacks of rodent PD models and discuss approaches to advance pre‐clinical PD research towards successful disease‐modifying therapy. © 2020 The Authors.

show abstract

“…These include the other members of the GDNF family, neurturin ( Horger et al, 1998 ), artemin ( Baloh et al, 1998 ) and persephin ( Milbrandt et al, 1998 ), VEGF proteins ( Piltonen et al, 2011 ), PDGF ( Pietz et al, 1996 ), PACAP ( Takei et al, 1998 ), members of TGFβ superfamily, including TGFβ 1, 2 and 3 ( Krieglstein et al, 1995a ), GDF5 ( Krieglstein et al, 1995b ) and GDF15 ( Strelau et al, 2000 ), FGF20 ( Ohmachi et al, 2003 ) and two more recently identified related factors CDNF and MANF ( Lindholm et al, 2007 , Petrova et al, 2003 ). Many of these factors have been reported to be protective for nigrostriatal neurons in animal models of Parkinson's Disease, including GDNF, neurturin, CDNF, MANF, PDGF, FGF20 and PACAP ( Lindholm et al, 2016 , Voutilainen et al, 2017 ). However, no obvious abnormal midbrain dopaminergic neuron phenotype has been reported in mice that lack any of these factors ( Lindahl et al, 2017 ), and where an abnormal phenotype was initially reported in mice with a conditional deletion of Gdnf in the striatum ( Pascual et al, 2008 ), comprehensive analysis of multiple mouse lines failed to find any abnormal dopaminergic phenotype ( Kopra et al, 2015 ).…”

Section: Discussionmentioning

confidence: 99%

TNF superfamily member APRIL enhances midbrain dopaminergic axon growth and contributes to the nigrostriatal projection in vivo

McWilliams

Howard

Wyatt

et al. 2017

Experimental Neurology

View full text Add to dashboard Cite

We have studied the role of the tumor necrosis factor superfamily member APRIL in the development of embryonic mouse midbrain dopaminergic neurons in vitro and in vivo. In culture, soluble APRIL enhanced axon growth during a window of development between E12 and E14 when nigrostriatal axons are growing to their targets in the striatum in vivo. April transcripts were detected in both the striatum and midbrain during this period and at later stages. The axon growth–enhancing effect of APRIL was similar to that of glial cell-derived neurotrophic factor (GDNF), but in contrast to GDNF, APRIL did not promote the survival of midbrain dopaminergic neurons. The effect of APRIL on axon growth was prevented by function-blocking antibodies to one of its receptors, BCMA (TNFRSF13A), but not by function-blocking antibodies to the other APRIL receptor, TACI (TNFRSF13B), suggesting that the effects of APRIL on axon growth are mediated by BCMA. In vivo, there was a significant reduction in the density of midbrain dopaminergic projections to the striatum in April −/− embryos compared with wild type littermates at E14. These findings demonstrate that APRIL is a physiologically relevant factor for the nigrostriatal projection. Given the importance of the degeneration of dopaminergic nigrostriatal connections in the pathogenesis and progression of Parkinson's disease, our findings contribute to our understanding of the factors that establish nigrostriatal integrity.

show abstract

Evidence for an Additive Neurorestorative Effect of Simultaneously Administered CDNF and GDNF in Hemiparkinsonian Rats: Implications for Different Mechanism of Action

Cited by 45 publications

References 54 publications

p58IPK Is an Endogenous Neuroprotectant for Retinal Ganglion Cells

p58IPK Is an Endogenous Neuroprotectant for Retinal Ganglion Cells

Back and to the Future: From Neurotoxin‐Induced to Human Parkinson's Disease Models

TNF superfamily member APRIL enhances midbrain dopaminergic axon growth and contributes to the nigrostriatal projection in vivo

Contact Info

Product

Resources

About