The Drosophila vesicular monoamine transporter reduces pesticide-induced loss of dopaminergic neurons

Lawal, Hakeem O.; Chang, Hui-Yun; Terrell, Ashley N.; Brooks, Elizabeth S.; Pulido, Dianne; Simon, Anne F.; Krantz, David E.

doi:10.1016/j.nbd.2010.05.008

Cited by 59 publications

(71 citation statements)

References 89 publications

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“…5B). This finding is similar to those of Lawal and coworkers (39), who found that overexpression of VMAT in Drosophila protected against the toxicity of a variety of pesticides linked to PD. HPLC analysis of transgenic TH-GAL4; UAS-dVMAT flies (i.e., those where VMAT was overexpressed in DA neurons) showed restoration of DA and DOPAC levels (Fig.…”

Section: Discussionsupporting

confidence: 91%

“…Indeed, we previously found that an increase in reactive oxygen species is observed in head extracts from 1-octen-3-ol-exposed flies (16). Previous studies modeling Parkinson disease in Drosophila demonstrated that overexpression of the vesicular monoamine transporter promotes packaging of dopamine into vesicles, thereby lowering its cytoplasmic concentrations (19,39). Human genetic studies have found that single nucleotide polymorphisms (SNPs) within the promoter region of VMAT2, in particular gain-of-function haplotypes, are also associated with decreased risk of PD in women (40).…”

Section: Discussionmentioning

confidence: 95%

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Fungal-derived semiochemical 1-octen-3-ol disrupts dopamine packaging and causes neurodegeneration

Inamdar

Hossain

Bernstein

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Parkinson disease (PD) is the most common movement disorder and, although the exact causes are unknown, recent epidemiological and experimental studies indicate that several environmental agents may be significant risk factors. To date, these suspected environmental risk factors have been man-made chemicals. In this report, we demonstrate via genetic, biochemical, and immunological studies that the common volatile fungal semiochemical 1-octen-3-ol reduces dopamine levels and causes dopamine neuron degeneration in Drosophila melanogaster. Overexpression of the vesicular monoamine transporter (VMAT) rescued the dopamine toxicity and neurodegeneration, whereas mutations decreasing VMAT and tyrosine hydroxylase exacerbated toxicity. Furthermore, 1-octen-3-ol also inhibited uptake of dopamine in human cell lines expressing the human plasma membrane dopamine transporter (DAT) and human VMAT ortholog, VMAT2. These data demonstrate that 1-octen-3-ol exerts toxicity via disruption of dopamine homeostasis and may represent a naturally occurring environmental agent involved in parkinsonism.building-related illness | mold | mushroom alcohol

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 95%

Fungal-derived semiochemical 1-octen-3-ol disrupts dopamine packaging and causes neurodegeneration

Inamdar

Hossain

Bernstein

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…5). This enhanced transmitter release and locomotion suggest elevated dopamine neurotransmission in these mice, a finding reflected in previous work on the overexpression of the Drosophila vesicular monoamine transporter (DVMAT-A) (31)(32)(33). Together with previous findings demonstrating reduced dopamine release and locomotion in VMAT2-deficient animals, the results from the VMAT2-HI mice suggest that there is a gene dosage-dependent regulation of vesicular capacity and dopamine output (21,41,42).…”

Section: Vmat2 Overexpression Increases Dopamine Release and Neurotrasupporting

confidence: 67%

“…Although the detrimental effects of reduced VMAT2 function are recognized, our understanding of the potential benefits of increased VMAT2 function in vivo has been limited to a Drosophila model (31)(32)(33). Thus, we generated VMAT2-overexpressing mice using a bacterial artificial chromosome (BAC) to determine whether increased vesicular packaging could provide an elevation of monoamine output in a mammalian system.…”

mentioning

confidence: 99%

Increased vesicular monoamine transporter enhances dopamine release and opposes Parkinson disease-related neurodegeneration in vivo

Lohr¹,

Bernstein²,

Stout³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

170

171

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Significance Several therapeutic strategies have been used to enhance monoamine neurotransmitter signaling. However, many of these interventions have deleterious side effects or lose effectiveness due to off-target actions and system feedback. These undesirable consequences likely occur because of temporal dysregulation of neurotransmitter release and uptake. We demonstrate that increasing vesicular packaging enhances dopamine neurotransmission without this signaling disruption. Mice with elevated vesicular monoamine transporter display increased dopamine release, improved outcomes on anxiety and depressive behaviors, enhanced locomotion, and protection from a Parkinson disease-related neurotoxic insult. The malleable nature of the dopamine vesicle suggests that interventions aimed at enhancing vesicle filling may be of therapeutic benefit.

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“…This early dysregulation could contribute to the later demise of the neurons, as dopamine has repeatedly shown to be toxic when it escapes normal regulatory mechanisms [43,44]. In support of this hypothesis, polymorphisms in genes involved in dopamine regulation, such as the vesicular and cytoplasmic dopamine transporters have been associated with changes in PD risk in humans and modulation of toxicity to dopamine neurons in experimental models [45,46], and lack of the vesicular transporter induces a loss of dopaminergic neurons in mice [47].…”

Section: Loss Of Striatal Dopamine Is Preceded By Increased Extracellmentioning

confidence: 95%

A Progressive Mouse Model of Parkinson's Disease: The Thy1-aSyn (“Line 61”) Mice

et al. 2012

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Identification of mutations that cause rare familial forms of Parkinson's disease (PD) and subsequent studies of genetic risk factors for sporadic PD have led to an improved understanding of the pathological mechanisms that may cause nonfamilial PD. In particular, genetic and pathological studies strongly suggest that alpha-synuclein, albeit very rarely mutated in PD patients, plays a critical role in the vast majority of individuals with the sporadic form of the disease. We have extensively characterized a mouse model over-expressing full-length, human, wild-type alpha-synuclein under the Thy-1 promoter. We have also shown that this model reproduces many features of sporadic PD, including progressive changes in dopamine release and striatal content, alphasynuclein pathology, deficits in motor and nonmotor functions that are affected in pre-manifest and manifest phases of PD, inflammation, and biochemical and molecular changes similar to those observed in PD. Preclinical studies have already demonstrated improvement with promising new drugs in this model, which provides an opportunity to test novel neuroprotective strategies during different phases of the disorder using endpoint measures with high power to detect drug effects.

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The Drosophila vesicular monoamine transporter reduces pesticide-induced loss of dopaminergic neurons

Cited by 59 publications

References 89 publications

Fungal-derived semiochemical 1-octen-3-ol disrupts dopamine packaging and causes neurodegeneration

Fungal-derived semiochemical 1-octen-3-ol disrupts dopamine packaging and causes neurodegeneration

Increased vesicular monoamine transporter enhances dopamine release and opposes Parkinson disease-related neurodegeneration in vivo

A Progressive Mouse Model of Parkinson's Disease: The Thy1-aSyn (“Line 61”) Mice

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