Modulatory effects of Cav1.3 calcium channels on dopamine homeostasis and alpha synuclein expression in a mouse model of Parkinson’s disease

In Parkinson’s disease (PD), mitochondrial dysfunction has been suggested to be an important pathogenetic factor whereby calcium and α-synuclein (aSYN) pathology facilitate the selective death of substantia nigra neurons. The present study aimed at investigating the modulatory effects of the voltage-gated calcium channels of subtype 1.3 (Cav1.3) on dopamine (DA) homeostasis and aSYN expression in Cav1.3 channel knockout mice under mitochondrial dysfunction induced by the neurotoxin 1-methyl-4- phenyl-1,2,3,6-tetrahydropyridine (MPTP). Following chronic MPTP treatment, tissue samples from the striatum and the midbrain were used for HPLC-based analysis of striatal DA and its metabolites, for the assessment of nigral mRNA levels of tyrosine hydroxylase (TH), dopamine transporter (DAT), and aSYN, as well as for Western blot detection of TH, DAT and aSYN protein in the striatum and the midbrain. Cav1.3 channel knockout mice displayed a decreased vulnerability to chronic MPTP exposure as measured by a rescue of striatal DA of ~50% and an unaffected DA turnover. This neuroprotective effect was paralleled by a preserved mRNA expression of nigral TH and DAT. However, such an effect could not be observed for the protein expression of striatal DAT nor for striatal and nigral aSYN protein when compared to MPTP-treated wild-type mice. Our data underline the pivotal role of Cav1.3 channels in the propagation of MPTP-induced breakdown of the nigro-striatal DA system. However, we could not confirm in-vivo evidence that aSYN expression is linked to calcium overload under the condition of mitochondrial dysfunction. For the first time we could demonstrate that genetic “silencing” of Cav1.3 channels in mice mitigates the toxic actions of chronic MPTP exposure, which so far has only been shown pharmacologically using non-selective calcium-channel blockers.

Author dc:creator

• Fei, Qingzhou

• Parkinson’s disease
• dopamine homeostasis
• α-synuclein
• Cav1.3 calcium channels
• tyrosine hydroxylase
• dopamine transporter

Licence dc:rights.uri

• http://www.fu-berlin.de/sites/refubium/rechtliches/Nutzungsbedingungen

Language dc:language

eng

Identifier URI

http://dx.doi.org/10.17169/refubium-43098

OAI record oai:identifier

https://refubium.fu-berlin.de/oai/request?verb=GetRecord&metadataPrefix=dim&identifier=oai%3Arefubium.fu-berlin.de%3Afub188%2F43382