Impaired dopamine release and synaptic plasticity in the striatum of Parkin−/− mice

Abstract

Parkin is the most common causative gene of juvenile and early-onset familial Parkinson's diseases and is thought to function as an E3 ubiquitin ligase in the ubiquitin-proteasome system. However, it remains unclear how loss of Parkin protein causes dopaminergic dysfunction and nigral neurodegeneration. To investigate the pathogenic mechanism underlying these mutations, we used parkin)/) mice to study its physiological function in the nigrostriatal circuit. Amperometric recordings showed decreases in evoked dopamine release in acute striatal slices of parkin)/) mice and reductions in the total catecholamine release and quantal size in dissociated chromaffin cells derived from parkin)/) mice. Intracellular recordings of striatal medium spiny neurons revealed impairments of long-term depression and long-term potentiation in parkin)/) mice, whereas long-term potentiation was normal in the Schaeffer collateral pathway of the hippocampus. Levels of dopamine receptors and dopamine transporters were normal in the parkin)/) striatum. These results indicate that Parkin is involved in the regulation of evoked dopamine release and striatal synaptic plasticity in the nigrostriatal pathway, and suggest that impairment in evoked dopamine release may represent a common pathophysiological change in recessive parkinsonism.

STEP61is a substrate of the E3 ligase parkin and is upregulated in Parkinson’s disease

“…STEP KO mice have elevated pERK1/2 and increased phosphorylation of synapsin I at ERK1/2-specific sites within presynaptic terminals (22), and phosphorylation of synapsin I at these sites is known to increase the probability of vesicle release (47). In this context, amperometric recordings in the striatum of PARK2 KO mice showed reduction in evoked dopamine release and impaired long-term potentiation and longterm depression in striatal MSNs (48), whereas similar analyses in KO mice for PINK-1 (an upstream regulator parkin) revealed decreases in evoked dopamine release in striatal slices (49).…”

Mitochondrial Quality Control Mediated by PINK1 and Parkin: Links to Parkinsonism

“…Loss of Parkin or Pink1 causes one phenotype similar to, albeit milder than, that in man, in which nigrostriatal dysfunction correlates with mitochondrial dysfunction in the striatum (Palacino et al 2004;Gautier et al 2008;Kitada et al 2009). Interestingly, PINK1 knock out (KO) mice also display pronounced cardiac hypertrophy (Billia et al 2011) and Parkin KO mice display less subcutaneous fat, are resistant to high-fat-diet-induced weight gain (Kim et al 2011a), and may be predisposed to hepatocellular carcinomas (Fujiwara et al 2008).…”

Modeling LRRK2 Parkinsonism

“…However, independent of the approach, a unifying theme is emerging from both invertebrate and vertebrate LRRK2 models, suggesting an important role for LRRK2 in dopaminergic neurotransmission, even in the absence of dopamine neuronal loss. Several other genetic PD mouse models also have abnormalities in dopamine transmission without neuronal loss including PINK1, parkin, DJ-1 and SNCA knockouts and SNCA WT over-expression mice (Abeliovich et al, 2000;Goldberg et al, 2003;Goldberg et al, 2005;Kitada et al, 2009;Nemani et al, 2010). Imaging studies have long established that in asymptomatic PD, the earliest detectable changes occur in the dopamine transporter and the same holds true for asymptomatic LRRK2 (Nandhagopal et al, 2008;Sossi et al, 2010) and SNCA patients (Bostantjopoulou et al, 2008;Perani et al, 2006;Samii et al, 1999).…”