Dopamine and Parkinson's disease: is the killer in the house?

Mf, Chesselet

doi:10.1038/sj.mp.4001289

Cited by 18 publications

(9 citation statements)

References 12 publications

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“…Our results support the involvement of endogenous DA in the special susceptibility of dopaminergic neurons to insults that may be responsible for development of PD (41). Knowledge about the way in which DA is involved in this process may lead to the possibility of new protection strategies against this important degenerative process.…”

Section: Discussionsupporting

confidence: 71%

Dopamine‐dependent neurotoxicity of lipopolysaccharide in substantia nigra

et al. 2004

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Intranigral injection of lipopolysaccharide (LPS), a potent inductor of inflammation, induces degeneration of dopaminergic neurons, along with an inflammatory process that features activation of microglial cells and loss of astrocytes. To test the involvement of dopamine (DA) in this degeneration induced by LPS, we treated albino Wistar rats with different concentrations of alpha-methyl-p-tyrosine (alpha-MPT), an inhibitor of tyrosine hydroxylase (TH) activity. Results showed that alpha-MPT prevented LPS-induced loss of TH immunostaining and expression of mRNA for TH and DA transporter; it also prevented substantial activation of microglial cells. Loss of the astroglial population, a marker of damage in our model, was also prevented. This protective effect resulted from inhibition of TH and the consequent decrease in DA concentration, because treatment with L-DOPA/benserazide, which bypasses TH inhibition induced by alpha-MPT, reversed the protective effect produced by this drug. These results point out the important contribution of DA to the vulnerability and degeneration of dopaminergic neurons of the substantia nigra. Knowledge about the involvement of DA in this process may lead to the possibility of new protection strategies against this important degenerative process.

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Section: Discussionsupporting

confidence: 71%

Dopamine‐dependent neurotoxicity of lipopolysaccharide in substantia nigra

et al. 2004

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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: 96%

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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“…However, such compensation would likely include increasing demands on the remaining dopamine neurons to uphold function. Given that dopamine itself is thought to contribute to neurodegeneration (Chesselet, 2003), it seems unlikely that this would provide neuroprotection. Indeed, our detailed regional analysis showed that this partial protection did not extend to the entire SNc.…”

Section: Discussionmentioning

confidence: 99%

“…Even though the disease may originate outside the brain and affects multiple central and peripheral neurons (Del Tredici and Braak, 2012), a characteristic feature of PD is the progressive loss of nigrostriatal dopaminergic neurons, leading to the motor deficits that define PD. Dopamine is prone to oxidation into reactive molecules that can cause oxidative stress; accordingly, disruption of dopamine homeostasis may contribute to the vulnerability of dopaminergic neurons (Chesselet, 2003, Hastings, et al, 1996). The cytoplasmic dopamine transporter (DAT), which recycles extracellular dopamine into dopamine terminals, contributes to the control of intracellular dopamine levels.…”

Section: Introductionmentioning

confidence: 99%

Effects of decreased dopamine transporter levels on nigrostriatal neurons and paraquat/maneb toxicity in mice

Richter¹,

Gabby²,

McDowell³

et al. 2017

Neurobiology of Aging

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How genetic variations in the dopamine transporter (DAT) combined with exposure to environmental toxins modulate the risk of Parkinson’s disease (PD) remains unclear. Using unbiased stereology in DAT knock-down mice (DAT-KD) and wild-type (WT) littermates we found that decreased DAT caused a loss of tyrosine hydroxylase-positive (dopaminergic) neurons in subregions of the substantia nigra pars compacta (SNc) at 3–4 days, 5 weeks, and 18 months of age. Both genotypes lost dopaminergic neurons with age and remaining neurons at 11 months were resilient to paraquat/maneb. In 5 weeks old mice, the toxins decreased SNc dopaminergic neurons in both genotypes but less in DAT-KD. Regional analysis revealed striking differences in the subsets of neurons affected by low DAT, paraquat/maneb, and aging. In particular, we show that a potentially protective effect of low DAT against toxin exposure is not sufficient to reduce death of all nigrostriatal dopaminergic neurons. Thus, different regional vulnerability of nigrostriatal dopaminergic neurons may contribute to an increased risk of developing PD when multiple factors are combined.

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Dopamine and Parkinson's disease: is the killer in the house?

Cited by 18 publications

References 12 publications

Dopamine‐dependent neurotoxicity of lipopolysaccharide in substantia nigra

Dopamine‐dependent neurotoxicity of lipopolysaccharide in substantia nigra

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

Effects of decreased dopamine transporter levels on nigrostriatal neurons and paraquat/maneb toxicity in mice

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