The parkin Mutant Phenotype in the Fly Is Largely Rescued by Metal-Responsive Transcription Factor (MTF-1)

Abstract

The gene for Parkin, an E3 ubiquitin ligase, is mutated in some familial forms of Parkinson's disease, a severe neurodegenerative disorder. A homozygous mutant of the Drosophila ortholog of human parkin is viable but results in severe motoric impairment including an inability to fly, female and male sterility, and a decreased life span. We show here that a double mutant of the genes for Parkin and the metal-responsive transcription factor 1 (MTF-1) is not viable. MTF-1, which is conserved from insects to mammals, is a key regulator of heavy metal homeostasis and detoxification and plays additional roles in other stress conditions, notably oxidative stress. In contrast to the synthetic lethality of the double mutant, elevated expression of MTF-1 dramatically ameliorates the parkin mutant phenotype, as evidenced by a prolonged life span, motoric improvement including short flight episodes, and female fertility. At the cellular level, muscle and mitochondrial structures are substantially improved. A beneficial effect is also seen with a transgene encoding human MTF-1. We propose that Parkin and MTF-1 provide complementary functions in metal homeostasis, oxidative stress and other cellular stress responses. Our findings also raise the possibility that MTF-1 gene polymorphisms in humans could affect the severity of Parkinson's disease.Parkinson's disease (PD) is the second most prevalent progressive neurodegenerative disorder and the most common age-related movement disorder (10,13,43,59). Many molecular aspects of PD pathogenesis still need to be clarified. Extensive studies point to oxidative stress as a major contributor to the disease (28). Besides the gene for Parkin, an E3 ubiquitin ligase, four other genes, PINK1, DJ1, UCHL1, and ␣-synuclein, have been implicated in rare, early-onset, familial forms of PD, whereas LRRK2 is predominantly responsible for late-onset PD (20,57,70). Much effort has gone into the development of animal models of PD, including models in the fly Drosophila melanogaster. In the studies presented here, we use a strain in which the ortholog of the human parkin gene has been disrupted by the insertion of a P-element transposon into the coding region (24,48).In mammals, the proteins PINK1 and Parkin cooperate to ensure proper quality control of mitochondria, and Parkin is particularly important for autophagy of faulty mitochondria (reviewed in references 8 and 73). In agreement with this notion, Parkin deficient flies suffer from mitochondrial malfunction (24, 45, 48), which distorts muscle structure and causes severe locomotor defects and an inability to fly (24, 48). Furthermore, both male and female parkin-null Drosophila mutants are sterile (52), exhibit an increased sensitivity to multiple stresses (including oxidative stress), and have a reduced life span (23, 48).Maintenance of metal homeostasis is an essential requirement for the proper functioning of all organisms. An adequate supply of essential trace metals, such as copper and zinc, is important, whereas an excess can be highly t...

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“…In line with the findings presented here, elevated expression of MTF-1 dramatically improved the condition of the parkin mutant (Saini et al, 2011). However, unlike the Ab transgenics described here where extra zinc was at least as bad, if not worse than copper, zinc supplementation had a strong beneficial effect on the parkin mutant .…”

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“…As previously reported, MTF1 binds specifically to heavy metal-responsive DNA sequence elements in the enhancer/promoter region of metallothionein (MT) genes to regulate their expression (26,27). MT genes, such as MT1X and MT2A, encode small cysteine-rich proteins that scavenge heavy metals, such as Zn (II), Cd (II) and Cu (I), and reactive oxygen species (28,29). Arriaga et al (30) found that the expression of 5 isoforms of MTs, consisting of MT1G, MT1E, MT1F, MT1H and MT1M, were lost during the transition between normal colorectal mucosa and CRC, and the expression of MTs was associated with a shorter survival time in CRC patients (30).…”

Loss of pdr-1/parkin influences Mn homeostasis through altered ferroportin expression in C. elegans

“…Previous in vitro evidence has shown that parkin can modulate levels of the 1B isoform of DMT1 through ubiquitination 32 . Moreover, Drosophila studies show that both pharmacological (BCS/BPD) or genetic (increased expression of the metal responsive transcription factor 1, MTF-1) chelation of redox-active metals decreases oxidative stress, improves reduced lifespan and normalizes metal concentrations in parkin mutant flies 33, 34 . Therefore, parkin’s regulation of metal homeostasis and its role as an E3 ligase raise the possibility of parkin-mediated regulation of Mn-responsive proteins.…”