Analysis of striatal transcriptome in mice overexpressing human wild-type alpha-synuclein supports synaptic dysfunction and suggests mechanisms of neuroprotection for striatal neurons

Cabeza-Arvelaiz, Yofre; Fleming, Sheila M.; Richter, Franziska; Masliah, Eliezer; Chesselet, Marie‐Françoise; Schiestl, Robert H.

doi:10.1186/1750-1326-6-83

Cited by 29 publications

(27 citation statements)

References 75 publications

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“…Alpha-synuclein overexpression disrupts transcription in the striatum of young Thy1-aSyn mice (Cabeza-Arvelaiz et al, 2011) and previous studies of substantia nigra pars compacta tissue in mice overexpressing alpha-synuclein under the tyrosine hydroxylase promoter showed extensive differences in genes involved in transcription or translation, as well as signal transduction (Miller et al, 2007). In mice over-expressing alpha-synuclein under the PDGF promoter (Yacoubian et al, 2008) changes were observed in a small number of genes at 3 months of age with increased alterations at 9 months.…”

Section: Resultsmentioning

confidence: 76%

Chronic administration of cholesterol oximes in mice increases transcription of cytoprotective genes and improves transcriptome alterations induced by alpha-synuclein overexpression in nigrostriatal dopaminergic neurons

Richter¹,

Gao²,

Medvedeva³

et al. 2014

Neurobiology of Disease

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Cholesterol-oximes TRO19622 and TRO40303 target outer mitochondrial membrane proteins and have beneficial effects in preclinical models of neurodegenerative diseases leading to their advancement to clinical trials. Dopaminergic neurons degenerate in Parkinson’s disease (PD) and are prone to oxidative stress and mitochondrial dysfunction. In order to provide insights into the neuroprotective potential of TRO19622 and TRO40303 for dopaminergic neurons in vivo, we assessed their effects on gene expression in laser captured nigrostriatal dopaminergic neurons of wildtype mice and of mice that over-express alpha-synuclein, a protein involved in both familial and sporadic forms of PD (Thy1-aSyn mice). Young mice were fed the drugs in food pellets or a control diet from 1 to 4 months of age, approximately 10 months before the appearance of striatal dopamine loss in this model. Unbiased weighted gene co-expression network analysis (WGCNA) of transcriptional changes revealed effects of cholesterol oximes on transcripts related to mitochondria, cytoprotection and anti-oxidant response in wild-type and transgenic mice, including increased transcription of stress defense (e.g. Prdx1, Prdx2, Glrx2, Hspa9, Pink1, Drp1, Trak1) and dopamine-related (Th, Ddc, Gch1, Dat, Vmat2, Drd2, Chnr6a) genes. Even at this young age transgenic mice showed alterations in transcripts implicated in mitochondrial function and oxidative stress (e.g. Bcl-2, Bax, Casp3, Nos2), and both drugs normalized about 20% of these alterations. Young Thy1-aSyn mice exhibit motor deficits that differ from parkinsonism and are established before the onset of treatment; these deficits were not improved by cholesterol oximes. However, high doses of TRO40303 improved olfaction and produced the same effects as dopamine agonists on a challenging beam test, specifically an increase in footslips, an observation congruent with its effects on transcripts involved in dopamine synthesis. High doses of TRO19622 increased alpha-synuclein aggregates in the substantia nigra; this effect, not seen with TRO40303 was inconsistent and may represent a protective mechanism as in other neurodegenerative diseases. Overall, the results suggest that cholesterol oximes, while not improving early effects of alpha-synuclein overexpression on motor behavior or pathology, may ameliorate the function and resilience of dopaminergic neurons in vivo and support further studies of neuroprotection in models with dopaminergic cell loss.

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Section: Resultsmentioning

confidence: 76%

Chronic administration of cholesterol oximes in mice increases transcription of cytoprotective genes and improves transcriptome alterations induced by alpha-synuclein overexpression in nigrostriatal dopaminergic neurons

Richter¹,

Gao²,

Medvedeva³

et al. 2014

Neurobiology of Disease

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“…By preventing the formation of amyloid beta fibrils, TTR may also play a neuroprotective role in degenerative diseases such as Alzheimer disease [29]. In connection with PD, Ttr is upregulated at a pre-manifest stage in the SNc of MPTP-treated monkeys [39] and in the striatum of mice overexpressing human α-synuclein gene [40], suggesting a role in compensatory processes. Ttr is also upregulated in response to nicotine [41], which, according to epidemiological data and studies in animal models, may protect against PD [42].…”

Section: Discussionmentioning

confidence: 99%

Striatal Molecular Signature of Subchronic Subthalamic Nucleus High Frequency Stimulation in Parkinsonian Rat

et al. 2013

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This study addresses the molecular mechanisms underlying the action of subthalamic nucleus high frequency stimulation (STN-HFS) in the treatment of Parkinson's disease and its interaction with levodopa (L-DOPA), focusing on the striatum. Striatal gene expression profile was assessed in rats with nigral dopamine neuron lesion, either treated or not, using agilent microarrays and qPCR verification. The treatments consisted in anti-akinetic STN-HFS (5 days), chronic L-DOPA treatment inducing dyskinesia (LIDs) or the combination of the two treatments that exacerbated LIDs. STN-HFS modulated 71 striatal genes. The main biological processes associated with the differentially expressed gene products include regulation of growth, of apoptosis and of synaptic transmission, and extracellular region is a major cellular component implicated. In particular, several of these genes have been shown to support survival or differentiation of striatal or of dopaminergic neurons. These results indicate that STN HFS may induce widespread anatomo-functional rearrangements in the striatum and create a molecular environment favorable for neuroprotection and neuroplasticity. STN-HFS and L-DOPA treatment share very few common gene regulation features indicating that the molecular substrates underlying their striatal action are mostly different; among the common effects is the down-regulation of Adrb1, which encodes the adrenergic beta-1- receptor, supporting a major role of this receptor in Parkinson's disease. In addition to genes already reported to be associated with LIDs (preprodynorphin, thyrotropin-releasing hormone, metabotropic glutamate receptor 4, cannabinoid receptor 1), the comparison between DOPA and DOPA/HFS identifies immunity-related genes as potential players in L-DOPA side effects.

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“…A broader investigation concerning a-synuclein was performed in silico; mice overexpressing human wild-type SNCA were used to perform a transcriptome analysis of the striatal brain region [171]. The expression of many genes implicated in apoptosis, cell cycle progression, neurogenesis and synaptic function were impaired, demonstrating that indeed a-synuclein is involved in many different cell processes that, when deregulated due to differential SNCA expression, may influence neurogenesis.…”

Section: Snca (Park1/park4)mentioning

confidence: 99%

Neural stem cells in Parkinson’s disease: a role for neurogenesis defects in onset and progression

Grand

Gonzalez-Cano

Pavlou

et al. 2014

Cell. Mol. Life Sci.

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Parkinson's disease (PD) is the second most common neurodegenerative disorder, leading to a variety of motor and non-motor symptoms. Interestingly, nonmotor symptoms often appear a decade or more before the first signs of motor symptoms. Some of these non-motor symptoms are remarkably similar to those observed in cases of impaired neurogenesis and several PD-related genes have been shown to play a role in embryonic or adult neurogenesis. Indeed, animal models deficient in Nurr1, Pitx3, SNCA and PINK1 display deregulated embryonic neurogenesis and LRRK2 and VPS35 have been implicated in neuronal development-related processes such as Wnt/bcatenin signaling and neurite outgrowth. Moreover, adult neurogenesis is affected in both PD patients and PD animal models and is regulated by dopamine and dopaminergic (DA) receptors, by chronic neuroinflammation, such as that observed in PD, and by differential expression of wild-type or mutant forms of PD-related genes. Indeed, an increasing number of in vivo studies demonstrate a role for SNCA and LRRK2 in adult neurogenesis and in the generation and maintenance of DA neurons. Finally, the roles of PDrelated genes, SNCA, LRRK2, VPS35, Parkin, PINK1 and DJ-1 have been studied in NSCs, progenitor cells and induced pluripotent stem cells, demonstrating a role for some of these genes in stem/progenitor cell proliferation and maintenance. Together, these studies strongly suggest a link between deregulated neurogenesis and the onset and progression of PD and present strong evidence that, in addition to a neurodegenerative disorder, PD can also be regarded as a developmental disorder.

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Analysis of striatal transcriptome in mice overexpressing human wild-type alpha-synuclein supports synaptic dysfunction and suggests mechanisms of neuroprotection for striatal neurons

Cited by 29 publications

References 75 publications

Chronic administration of cholesterol oximes in mice increases transcription of cytoprotective genes and improves transcriptome alterations induced by alpha-synuclein overexpression in nigrostriatal dopaminergic neurons

Chronic administration of cholesterol oximes in mice increases transcription of cytoprotective genes and improves transcriptome alterations induced by alpha-synuclein overexpression in nigrostriatal dopaminergic neurons

Striatal Molecular Signature of Subchronic Subthalamic Nucleus High Frequency Stimulation in Parkinsonian Rat

Neural stem cells in Parkinson’s disease: a role for neurogenesis defects in onset and progression

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