Impaired dopamine release and synaptic plasticity in the striatum of PINK1 -deficient mice

Abstract

Parkinson's disease (PD) is characterized by the selective vulnerability of the nigrostriatal dopaminergic circuit. Recently, loss-offunction mutations in the PTEN-induced kinase 1 (PINK1) gene have been linked to early-onset PD. How PINK1 deficiency causes dopaminergic dysfunction and degeneration in PD patients is unknown. Here, we investigate the physiological role of PINK1 in the nigrostriatal dopaminergic circuit through the generation and multidisciplinary analysis of PINK1 ؊/؊ mutant mice. We found that numbers of dopaminergic neurons and levels of striatal dopamine (DA) and DA receptors are unchanged in PINK1 ؊/؊ mice. Amperometric recordings, however, revealed decreases in evoked DA release in striatal slices and reductions in the quantal size and release frequency of catecholamine in dissociated chromaffin cells. Intracellular recordings of striatal medium spiny neurons, the major dopaminergic target, showed specific impairments of corticostriatal long-term potentiation and long-term depression in PINK1 ؊/؊ mice. Consistent with a decrease in evoked DA release, these striatal plasticity impairments could be rescued by either DA receptor agonists or agents that increase DA release, such as amphetamine or L-dopa. These results reveal a critical role for PINK1 in DA release and striatal synaptic plasticity in the nigrostriatal circuit and suggest that altered dopaminergic physiology may be a pathogenic precursor to nigrostriatal degeneration.neurodegeneration ͉ Parkinson's disease ͉ substantia nigra P arkinson's disease (PD) is the most common movement disorder and is characterized by bradykinesia, rigidity, resting tremor, and postural instability. These clinical features are thought to result from reduced dopaminergic input to the striatum and the loss of dopaminergic neurons in the pars compacta of the substantia nigra (SNpc). Although the occurrence of PD is largely sporadic, mutations in five distinct genes have been linked to clinical syndromes that are often indistinguishable from sporadic PD. Of these, mutations in the parkin, DJ-1, and PINK1 (PTEN induced kinase 1) genes are recessively inherited and include large exonic deletions or frame-shift truncations, suggesting a loss-of-function pathogenic mechanism (1-3).PINK1 was originally identified as a gene whose transcription was activated by the tumor suppressor PTEN in carcinoma cell lines (4). The PINK1 gene has eight exons spanning 1.8 kb and encodes 581 aa residues. The deduced amino acid sequence indicates that PINK1 contains a mitochondrial targeting motif (amino acids 1-34) and a kinase domain (amino acids 156-509) that is highly homologous to Ca 2ϩ /calmodulin-dependent kinases. Since the first report linking recessively inherited nonsense (W437X) and missense (G309D) mutations in PINK1 to familial PARK6 cases (3), large numbers (Ͼ30) of additional truncation and missense mutations have been identified in early-onset PD cases with or without family history (5-11). Genetic analysis revealed that homozygous and compound heterozygous mutatio...

PTEN-inducible kinase 1 (PINK1)/Park6 is indispensable for normal heart function

“…The generation of the PINK1 gene-deficient mice was previously described (30). Age-matched syngenic male PINK1 +/+, +/−, −/− mice (10-12 wk, 22-26 g) were used in this study.…”

A Dimeric PINK1-containing Complex on Depolarized Mitochondria Stimulates Parkin Recruitment

“…Factors that regulate mitochondrial morphology have been shown to interact genetically with pink1 (5-7), and the pink1-deficient phenotype in Drosophila can be rescued by a component of the mitochondrial electron transport chain complex or a mitochondrial electron carrier (8,9). Respiratory chain defects have been reported in Pink1 Ϫ/Ϫ mouse embryonic fibroblasts (10), and some morphological and functional defects of mitochondria have been observed in the striatum of Pink1 null mice; Pink1 knock-out mice, however, do not exhibit any obvious morphological changes or loss of dopaminergic neurons in the substantia nigra (11,12). These findings indicate that PINK1 contributes to mitochondrial integrity.…”

Physiology versus pathology in Parkinson's disease

“…Because the measurements in this preparation reflect reuptake as well as release, the normalization of release by blocking reuptake in DJ-1-deficient mice suggests increased activity of the dopamine transporter, whereas the relative lack of effect in PINK1 knockouts suggests a primary defect in the release mechanism. Indeed, mice lacking PINK1 show less frequent as well as smaller individual release events from adrenal chromaffin cells (5). The authors further demonstrate defects in plasticity at the corticostriatal synapse that can be corrected with dopamine receptor agonists, dopamine supplementation, and amphetamine, supporting a specific, presynaptic defect in dopaminergic neurotransmission.…”

“…Similar to the DJ-1 knockout, PINK1-deficient mice show defects in evoked dopamine release measured by using striatal slices (5). However, these defects appear to differ, with inhibition of dopamine reuptake apparently normalizing the defect in release in the DJ-1 knockouts but not in the PINK1 (5,10,11). Because the measurements in this preparation reflect reuptake as well as release, the normalization of release by blocking reuptake in DJ-1-deficient mice suggests increased activity of the dopamine transporter, whereas the relative lack of effect in PINK1 knockouts suggests a primary defect in the release mechanism.…”

“…In summary, the work of Kitada et al (5) provides yet another example of a defect in dopamine release in a recessive form of PD, raising the provocative hypothesis that this defect contributes to, rather than simply reflects, the degenerative process. Future work will need to characterize in more detail the effects of recessive PD genes on mitochondria in mammalian systems and to address the relationship between mitochondrial function and transmitter release.…”