Parkin-deficient Mice Exhibit Nigrostriatal Deficits but Not Loss of Dopaminergic Neurons*

By M. Goldberg, S. Fleming, J. Palacino, C. Cepeda, H. Lam, A. Bhatnagar, E. Meloni, Nanping Wu, L. Ackerson, G. J. Klapstein and 6 more. Journal of Biological Chemistry, 2003

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Loss-of-function mutations in parkin are the major cause of early-onset familial Parkinson's disease. To investigate the pathogenic mechanism by which loss of parkin function causes Parkinson's disease, we generated a mouse model bearing a germline disruption in parkin. Parkin–/– mice are viable and exhibit grossly normal brain morphology. Quantitative in vivo microdialysis revealed an increase in extracellular dopamine concentration in the striatum of parkin–/– mice. Intracellular recordings of medium-sized striatal spiny neurons showed that greater currents are required to induce synaptic responses, suggesting a reduction in synaptic excitability in the absence of parkin. Furthermore, parkin–/– mice exhibit deficits in behavioral paradigms sensitive to dysfunction of the nigrostriatal pathway. The number of dopaminergic neurons in the substantia nigra of parkin–/– mice, however, is normal up to the age of 24 months, in contrast to the substantial loss of nigral neurons characteristic of Parkinson's disease. Steady-state levels of CDCrel-1, synphilin-1, and α-synuclein, which were identified previously as substrates of the E3 ubiquitin ligase activity of parkin, are unaltered in parkin–/– brains. Together these findings provide the first evidence for a novel role of parkin in dopamine regulation and nigrostriatal function, and a non-essential role of parkin in the survival of nigral neurons in mice.

Subfields: Cellular and Molecular Neuroscience, Neurology

View Paper: https://www.semanticscholar.org/paper/8413b98570fe90525772440901a6b3b7bd93317a

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Citations in the corpus

Cellular mitophagy: Mechanism, roles in diseases and small molecule pharmacological regulation (2023, result): “According to previous research, Parkin KO animals had abnormal nigrostriatal pathway function, reduced synaptic excitability in spiny neurons, and an increase in extracellular dopamine concentration in the striatum [62].”
PARIS (ZNF746) Repression of PGC-1α Contributes to Neurodegeneration in Parkinson’s Disease (2011, positive): “Dopaminergic Degeneration in Conditional Parkin KO Mice Germline deletion of parkin using a variety of approaches created parkin KO mice with minimal phenotypes and no loss of DA neurons (Goldberg et al., 2003; Von Coelln et al., 2004).”
Molecular pathophysiology of Parkinson's disease. (2005, background): “Two of the knockouts show subtle behavioral deficits, mild alterations of dopaminergic and glutamatergic neurotransmission, and abnormalities in dopamine metabolism (Goldberg et al. 2003, Itier et al. 2003).”
Dopamine covalently modifies and functionally inactivates parkin (2005, background): “2b ), whose immunospecificity has been established in independent report”
A new pathway for mitochondrial quality control: mitochondrial‐derived vesicles (2014, background): “However, the loss of PINK1 or Parkin in mice leads to very mild phenotypes and a notable absence of neurodegeneration (Goldberg et al, 2003; Kitada et al, 2009).”
Expanding insights of mitochondrial dysfunction in Parkinson's disease (2006, background): “Intriguingly, parkin deficiency in these mice did not cause dopaminergic degeneration, which is also observed in exon 2 and other exon 3 deletion model”
Autophagy maintains the metabolism and function of young and old (hematopoietic) stem cells (2017, background): “Further characterization of Park2−/− mice also revealed no similarities to the phenotypes of Atg12cKO mice, and normal function of Park2−/− HSCs in transplantation experiments (Extended Data Fig.”
The Roles of PINK1, Parkin and Mitochondrial Fidelity in Parkinson's Disease (2015, background): “The first two Parkin-KO mouse models lacked exon 3 and exhibited only mild phenotypes, such as the disruption of fine motor skills and slight abnormalities in dopamine metabolism and release, but, disappointingly, no dopaminergic neuron loss (Goldberg et al., 2003; Itier et al., 2003).”
Cell biology of protein misfolding: The examples of Alzheimer's and Parkinson's diseases (2004, background): “Several substrates for the ubiquitin-ligase function of Parkin have been suggested, but there is no agreement as to which of these are bona fide substrates in vivo , as homozygous deletion of Parkin in mice does not seem to elevate brain levels of these proteins, although it also does not produce”
Dopamine release in the basal ganglia (2011, background): “Interestingly, striatal [DA] o monitored in vivo using microdialysis are slightly elevated in parkin−/− mice (Goldberg et al., 2003), indicating that other processes, e.g., DA neuron activity, contribute to basal levels.”