Increased Dopaminergic Neuron Sensitivity to 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine (MPTP) in Transgenic Mice Expressing Mutant A53T α-Synuclein

Yu, Wen H.; Matsuoka, Yasuji; Sziráki, István; Hashim, Audrey; LaFrancois, John; Sershen, Henry; Duff, Karen

doi:10.1007/s11064-007-9533-4

Cited by 39 publications

(29 citation statements)

References 67 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Data expressed as means ± SEM. Asterisk denotes statistical significance (*p<0.05) this area is vulnerable to complex I inhibition (Yu et al 2008). Our study demonstrated increased αSN immunoreactivity in the frontal cortex from rotenone-treated transgenic hA53T αSN mice.…”

Section: Discussionmentioning

confidence: 99%

α-Synuclein Transgenic Mice Reveal Compensatory Increases in Parkinson's Disease-Associated Proteins DJ-1 and Parkin and Have Enhanced α-Synuclein and PINK1 Levels After Rotenone Treatment

et al. 2010

View full text Add to dashboard Cite

Parkinson's disease (PD) is a severe neurodegenerative disorder characterised by loss of dopaminergic neurons of the substantia nigra. The pathological hallmarks are cytoplasmic inclusions termed Lewy bodies consisting primarily of aggregated alpha-synuclein (alphaSN). Different lines of transgenic mice have been developed to model PD but have failed to recapitulate the hallmarks of this disease. Since treatment of rodents with the pesticide rotenone can reproduce nigrostriatal cell loss and other features of PD, we aimed to test chronic oral administration of rotenone to transgenic mice over-expressing human alphaSN with the A53T mutation. Initial assessment of this transgenic line for compensatory molecular changes indicated decreased brain beta-synuclein expression and significantly increased levels of the PD-associated oxidative stress response protein, DJ-1, and the E3 ubiquitin ligase enzyme, Parkin. Rotenone treatment of 30 mg/kg for 25 doses over a 35-day period was tolerated in the transgenic mice and resulted in decreased spontaneous locomotor movement and increased cytoplasmic alphaSN expression. The mitochondrial Parkinson's-associated PTEN-induced kinase 1 protein levels were also increased in transgenic mouse brain after rotenone treatment; there was no change in brain dopamine levels or nigrostriatal cell loss. These hA53T alphaSN transgenic mice provide a useful model for presymptomatic Parkinson's features and are valuable for study of associated compensatory changes in early Parkinson's disease stages.

show abstract

Section: Discussionmentioning

confidence: 99%

α-Synuclein Transgenic Mice Reveal Compensatory Increases in Parkinson's Disease-Associated Proteins DJ-1 and Parkin and Have Enhanced α-Synuclein and PINK1 Levels After Rotenone Treatment

et al. 2010

View full text Add to dashboard Cite

show abstract

“…6-Hydroxydopamine toxicity seems to be influenced by alpha-synuclein, since alpha-synuclein-deleted mice are more resistant against 6-hydroxydopamine than their wild type (Alvarez-Fischer et al 2008). Transgenic mice expressing human mutant A53T alpha-synuclein sensitizes dopaminergic neurons to neurotoxic insults and is associated with greater oxidative stress (Yu et al 2008). Early microglial activation with concomitant increase in proinflammatory molecules in mice that over-express wildtype SYN was observed (Su et al 2008).…”

Section: Alpha-synuclein and Parkinson's Diseasementioning

confidence: 97%

Molecular and Neurochemical Mechanisms in PD Pathogenesis

Paris¹,

Lozano²,

Perez-Pastene³

et al. 2009

Neurotox Res

View full text Add to dashboard Cite

Oxidation of dopamine to aminochrome seems to be a normal process leading to aminochrome polymerization to form neuromelanin, since normal individuals have this pigment in their dopaminergic neurons in the substantia nigra. The neurons lost in individuals with Parkinson's disease are dopaminergic neurons containing neuromelanin. This raises two questions. First, why are those cells containing neuromelanin lost in this disease? Second, what is the identity of the neurotoxin that induces this cell death? We propose that aminochrome is the agent responsible for the death of dopaminergic neurons containing neuromelanin in individuals with Parkinson's disease. The normal oxidative pathway of dopamine, in which aminochrome polymerizes to form neuromelanin, can be neurotoxic if DT-diaphorase is inhibited under certain conditions. Inhibition of DT-diaphorase allows two neurotoxic reactions to proceed: (i) the formation of aminochrome adducts with alpha-synuclein, which induce and stabilize the formation of neurotoxic protofibrils; and (ii) the one electron reduction of aminochrome to the neurotoxic leukoaminochrome o-semiquinone radical. Therefore, we propose that DT-diaphorase is an important neuroprotective enzyme in dopaminergic neurons containing neuromelanin.

show abstract

“…With respect to the high tolerance of LUHMES towards overexpression of wildtype ASYN, it needs to be discussed that ASYN indeed is not necessarily a cytotoxic protein. Transgenic mice, overexpressing ASYN or its mutant forms (e.g., A30P, A53T), usually do not show neurodegeneration, but some reports indicate an elevated susceptibility following exposure to neurotoxic conditions such as MPTP treatment (Dong et al, 2002;Nieto et al, 2006;Yu et al, 2008). However, others could not detect different susceptibilities between wildtype and ASYN overexpressing mice (Rathke-Hartlieb et al, 2001).…”

Section: Inhibition Of Mitochondrial Movement In Neurites As Early Efmentioning

confidence: 99%

Generation of genetically-modified human differentiated cells for toxicological tests and the study of neurodegenerative diseases

Schildknecht

Karreman

Pöltl

et al. 2013

ALTEX

View full text Add to dashboard Cite

Summary -phenylpyridinium (MPP + ). Different lentiviral constructs then were tested: cells labeled ubiquitously with green (GFP) or red fluorescent protein (RFP) allowed the quantification of neurite growth and of its disturbance by toxicants; expression of proteins of interest could be targeted to different organelles; production of two different proteins from a single read-through construct was achieved successfully by an expression strategy using a linker peptide between the two proteins, which is cleaved by deubiquitinases; LUHMES, labeled with GFP in the cytosol and RFP in the mitochondria

show abstract

Increased Dopaminergic Neuron Sensitivity to 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine (MPTP) in Transgenic Mice Expressing Mutant A53T α-Synuclein

Cited by 39 publications

References 67 publications

α-Synuclein Transgenic Mice Reveal Compensatory Increases in Parkinson's Disease-Associated Proteins DJ-1 and Parkin and Have Enhanced α-Synuclein and PINK1 Levels After Rotenone Treatment

α-Synuclein Transgenic Mice Reveal Compensatory Increases in Parkinson's Disease-Associated Proteins DJ-1 and Parkin and Have Enhanced α-Synuclein and PINK1 Levels After Rotenone Treatment

Molecular and Neurochemical Mechanisms in PD Pathogenesis

Generation of genetically-modified human differentiated cells for toxicological tests and the study of neurodegenerative diseases

Contact Info

Product

Resources

About