Abstract
BackgroundMutations in the gene encoding the E3 ubiquitin ligase parkin (PARK2) are responsible for the majority of autosomal recessive parkinsonism. Similarly to other knockout mouse models of PD-associated genes, parkin knockout mice do not show a substantial neuropathological or behavioral phenotype, while loss of parkin in Drosophila melanogaster leads to a severe phenotype, including reduced lifespan, apoptotic flight muscle degeneration and male sterility. In order to study the function of parkin in more detail and to address possible differences in its role in different species, we chose Danio rerio as a different vertebrate model system.Methodology/Principal FindingsWe first cloned zebrafish parkin to compare its biochemical and functional aspects with that of human parkin. By using an antisense knockdown strategy we generated a zebrafish model of parkin deficiency (knockdown efficiency between 50% and 60%) and found that the transient knockdown of parkin does not cause morphological or behavioral alterations. Specifically, we did not observe a loss of dopaminergic neurons in parkin-deficient zebrafish. In addition, we established transgenic zebrafish lines stably expressing parkin by using a Gal4/UAS-based bidirectional expression system. While parkin-deficient zebrafish are more vulnerable to proteotoxicity, increased parkin expression protected transgenic zebrafish from cell death induced by proteotoxic stress.Conclusions/SignificanceSimilarly to human parkin, zebrafish parkin is a stress-responsive protein which protects cells from stress-induced cell death. Our transgenic zebrafish model is a novel tool to characterize the protective capacity of parkin in vivo.
Highlights
Parkinson’s Disease (PD), the second most common neurodegenerative disease after Alzheimer’s Disease, is characterized primarily by the progressive loss of dopaminergic neurons in the substantia nigra and subsequent dopamine depletion in the striatum
Zebrafish parkin shows the same biochemical and functional features as human parkin: It is transcriptionally up-regulated in response to cellular stress and protects from stress-induced cell death
In line with these findings, zebrafish parkin adopts a detergent-insoluble conformation and forms cellular aggregates in cells treated with hydrogen peroxide or dopamine
Summary
Parkinson’s Disease (PD), the second most common neurodegenerative disease after Alzheimer’s Disease, is characterized primarily by the progressive loss of dopaminergic neurons in the substantia nigra and subsequent dopamine depletion in the striatum. Mutations in the genes encoding a-synuclein and LRRK2 (leucinerich repeat kinase 2) are responsible for autosomal dominant forms of PD, presumably by a gain-of-function mechanism. Loss-of-function mutations in the genes encoding parkin, PINK1, and DJ-1 mediate autosomal recessive PD. Sporadic and monogenic forms share important clinical, pathological and biochemical features, notably the progressive demise of dopaminergic neurons in the substantia nigra. Insight into the function and dysfunction of PDassociated gene products can help to elucidate the underlying mechanisms leading to neuronal cell death. Mutations in the gene encoding the E3 ubiquitin ligase parkin (PARK2) are responsible for the majority of autosomal recessive parkinsonism.
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