Increased Physiological GDNF Levels Have No Effect on Dopamine Neuron Protection and Restoration in a Proteasome Inhibition Mouse Model of Parkinson’s Disease

Abstract

Parkinson’s disease (PD) is a progressive neurodegenerative disease that comprises a range of motor and non-motor symptoms. Glial cell line-derived neurotrophic factor (GDNF) promotes the survival of dopamine neuronsin vitroandin vivo, and intracranial delivery of GDNF has been tested in six clinical trials for treating PD. However, clinical trials with ectopic GDNF have yielded variable results, which could in part result from abnormal expression site and levels caused by ectopic overexpression. Therefore, an important open question is whether an increase in endogenous GDNF expression could be potent in reversing PD progression. Here, we tested the therapeutic potential of endogenous GDNF using mice in which endogenous GDNF can be conditionally upregulated specifically in cells that express GDNF naturally (conditional GDNF hypermorphic mice;GdnfcHyper). We analyzed the impact of endogenous GDNF upregulation in both neuroprotection and neurorestoration procedures, and for both motor and non-motor symptoms in the proteasome inhibitor lactacystin (LC) model of PD. Our results showed that upregulation of endogenous GDNF in the adult striatum is not protective in LC-induced PD model in mice. Since age is the largest risk factor for PD, we also analyzed the effect of deletion of endogenous GDNF in agedGdnfconditional knock-out mice. We found that GDNF deletion does not increase susceptibility to LC-induced damage. We conclude that endogenous GDNF does not impact the outcome in the LC-induced proteasome inhibition mouse model of Parkinson’s disease.Significance StatementGlial cell line-derived neurotrophic factor GDNF is a strong enhancer of dopamine neuron function and survival. Ectopic delivery of GDNF has been tested in six clinical trials to treat Parkinson’s disease with promising but inconclusive results. Whether an increase in endogenous GDNF expression could be more beneficial in protecting or restoring damaged dopamine neurons than ectopic GDNF delivery has remained unknown. Here, we use GDNF conditional hypermorph and GDNF conditional knock-out mice to study the role of endogenous GDNF in a mouse model of Parkinson’s disease. Our findings demonstrate that neither an increase or loss of endogenous GDNF expression impacts dopamine neuron survival and recovery in proteasome inhibition model of Parkinson’s disease.

Opposing Spatially Segregated Function of Endogenous GDNF-RET Signaling in Cocaine Addiction

“…Here we injected AAV-Cre, this time into the NAc of GDNF cKO animals [49], to specifically target accumbal GDNF (Figure 3A). As shown on Figure 3B, Gdnf mRNA expression, which is known to correspond to GDNF protein level in mouse brain and other tissues [38,39,49,52] was successfully reduced by about 70-80% in the NAc via AAV-Cre injections. We next followed extinction over the next month before administering half the original dose of cocaine to reinstate preference (Figure 3A).…”

Analysis of Acute and Chronic Methamphetamine Treatment in Mice on Gdnf System Expression Reveals a Potential Mechanism of Schizophrenia Susceptibility

“…Hence, here we performed an exploratory study to see if and how methamphetamine, applied at the doses and application regimen used in the above studies to induce SCZ-like behavior in animals, induces and modulates the expression of genes related to the GDNF system. As multiple studies reveal that Gdnf mRNA levels correlate with GDNF protein levels in the mouse brain [ 2 , 14 , 73 , 74 ], in this current exploratory study, we decided to measure Gdnf mRNA levels. Additionally, previous studies have demonstrated that Gfra1 and Ret mRNA levels also correlate with protein levels in mice [ 75 , 76 , 77 , 78 ].…”