Abstract
Mutations in the PARK2 gene encoding the protein parkin cause autosomal recessive juvenile parkinsonism (ARJP), a neurodegenerative disease characterized by early dysfunction and loss of dopamine (DA) neurons in the substantia nigra pars compacta (SNc). No therapy is currently available to prevent or slow down the neurodegeneration in ARJP patients. Preclinical models are key to clarifying the early events that lead to neurodegeneration and reveal the potential of novel neuroprotective strategies. ParkinQ311X is a transgenic mouse model expressing in DA neurons a mutant parkin variant found in ARJP patients. This model was previously reported to show the neuropathological hallmark of the disease, i.e., the progressive loss of DA neurons. However, the early dysfunctions that precede neurodegeneration have never been investigated. Here, we analyzed SNc DA neurons in parkinQ311X mice and found early features of mitochondrial dysfunction, extensive cytoplasmic vacuolization, and dysregulation of spontaneous in vivo firing activity. These data suggest that the parkinQ311X mouse recapitulates key features of ARJP and provides a useful tool for studying the neurodegenerative mechanisms underlying the human disease and for screening potential neuroprotective drugs.
Highlights
Mutations in the PARK2 gene encoding the protein parkin are the most frequent cause of autosomal recessive juvenile parkinsonism (ARJP) (OMIM# 600116)
At 1 month of age, the number of substantia nigra pars compacta (SNc) DA neurons was similar in transgenic mice and their WT littermates, whereas at 6 and 12 months of age, parkinQ311X mice showed a reduction of 23% and
25% in DA neurons, respectively (Figure 1a shows representative immunofluorescence images with TH labeling in the SNc of WT and parkinQ311X mice at 1, 6, and 12 months of age; Figure 1b shows the results of the stereological count and one-way ANOVA, followed by Sidak’s multiple comparisons test F = 5.998)
Summary
Mutations in the PARK2 gene encoding the protein parkin are the most frequent cause of autosomal recessive juvenile parkinsonism (ARJP) (OMIM# 600116). Since some PARK2 patients bear point mutations that lead to the expression of mutant parkin forms [1], the study of transgenic mice overexpressing pathological parkin variants has been proposed as an attractive alternative to parkin deficiency models for understanding neurodegeneration and developing novel therapeutics [6,7,8]. ParkinQ311X is a bacterial artificial chromosome (BAC) transgenic mouse expressing a C-terminal truncated human mutant parkin found in ARJP kindred under the DA transporter (DAT) promoter [7] This parkinQ311X model exhibits SNc DA neuron degeneration at 6 [9] and 16 [7] months of age. We analyzed the time course of nigrostriatal neurodegeneration and identified a time window with no overt neurodegeneration At this time-point, we analyzed neuronal activity and mitochondrial morphology in the search for an early dysfunction of DA neurons. PARK2 mutations, such as mitochondrial defects [10,11], cytoplasmic vacuolization [12], and abnormal bursting activity [13]
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