Expression Profiling of Substantia Nigra in Parkinson Disease, Progressive Supranuclear Palsy, and Frontotemporal Dementia With Parkinsonism

Hauser, Michael A.; Li, Yi-Ju; Xu, Hong; Noureddine, Maher; Shao, Yujun S.; Gullans, Steven R.; Scherzer, Clemens R.; Jensen, Roderick V.; McLaurin, Adam C.; Gibson, Jason; Scott, Burton L.; Jewett, Rita; Stenger, Judith E.; Schmechel, Donald E.; Hulette, Christine M.; Vance, Jeffery M.

doi:10.1001/archneur.62.6.917

Cited by 153 publications

(130 citation statements)

References 23 publications

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“…Here, we describe gene regulatory relationships between SNCA and two other pathways considered to be of relevance in PD, dopamine synthesis and parkin metabolism. Supplemental File 6 provides a comparison of our gene list with findings from other microarray studies in SN of sporadic PD (see [22,23,43,75]). …”

Section: Discussionmentioning

confidence: 99%

Analysis of alpha-synuclein, dopamine and parkin pathways in neuropathologically confirmed parkinsonian nigra

et al. 2007

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The identification of mutations that cause familial Parkinson's disease (PD) provides a framework for studies into pathways that may be perturbed also in the far more common, non-familial form of the disorder. Following this hypothesis, we have examined the gene regulatory network that links alpha-synuclein and parkin pathways with dopamine metabolism in neuropathologically verified cases of sporadic PD. By means of an in silico approach using a database of eukaryotic molecular interactions and a whole genome transcriptome dataset validated by qRT-PCR and histological methods, we found parkin and functionally associated genes to be upregulated in the lateral substantia nigra (SN). In contrast, alpha-synuclein and ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) gene expression levels were significantly reduced in both the lateral and medial SN in PD. Gene expression for Septin 4, a member of the GTP-binding protein family involved in alpha-synuclein metabolism was elevated in the lateral parkinsonian SN. Additionally, catalase and mitogen-activated protein kinase 8 and poly (ADP-ribose) polymerase family member 1 (PARP1) known to function in DNA repair and cell death induction, all members of the dopamine synthesis pathway, were up-regulated in the lateral SN. In contrast, two additional PD-linked genes, glucocerebrosidase and nuclear receptor subfamily 4, group A, member 2 (NR4A2) showed reduced expression. We show that in sporadic PD, parkin, alpha-synuclein and dopamine pathways are co-deregulated. Alpha-synuclein is a member of all three gene regulatory networks. Our analysis results support the view that alpha-synuclein has a central role in the familial as well as the non-familial form of the disease and provide steps towards a pathway definition of PD.

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Section: Discussionmentioning

confidence: 99%

Analysis of alpha-synuclein, dopamine and parkin pathways in neuropathologically confirmed parkinsonian nigra

et al. 2007

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“…Furthermore, Hsp70 has been shown to enhance α-synuclein refolding or degradation, thereby decreasing α-synuclein fibrillization and toxicity (Klucken et al 2004;Luk et al 2008). There is an increase in the expression of HSPA1A and HSPA1B in the substantia nigra of patients with Parkinson's disease, progressive supranuclear palsy, and frontotemporal dementia with parkinsonism (Hauser et al 2005). In their report, Hauser and colleagues further suggested that Hsp70 induction was a "common response to mitigate the toxic effects of misfolded protein."…”

Section: Heat Shock Proteins In Neurodegenerative Disorders and Agingmentioning

confidence: 99%

Heat shock proteins in neurodegenerative disorders and aging

Leak

2014

J. Cell Commun. Signal.

145

119

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Many members of the heat shock protein family act in unison to refold or degrade misfolded proteins. Some heat shock proteins also directly interfere with apoptosis. These homeostatic functions are especially important in proteinopathic neurodegenerative diseases, in which specific proteins misfold, aggregate, and kill cells through proteotoxic stress. Heat shock protein levels may be increased or decreased in these disorders, with the direction of the response depending on the individual heat shock protein, the disease, cell type, and brain region. Aging is also associated with an accrual of proteotoxic stress and modulates expression of several heat shock proteins. We speculate that the increase in some heat shock proteins in neurodegenerative conditions may be partly responsible for the slow progression of these disorders, whereas the increase in some heat shock proteins with aging may help delay senescence. The protective nature of many heat shock proteins in experimental models of neurodegeneration supports these hypotheses. Furthermore, some heat shock proteins appear to be expressed at higher levels in longer-lived species. However, increases in heat shock proteins may be insufficient to override overwhelming proteotoxic stress or reverse the course of these conditions, because the expression of several other heat shock proteins and endogenous defense systems is lowered. In this review we describe a number of stressinduced changes in heat shock proteins as a function of age and neurodegenerative pathology, with an emphasis on the heat shock protein 70 (Hsp70) family and the two most common proteinopathic disorders of the brain, Alzheimer's and Parkinson's disease.

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“…In brief, total RNA was used for cDNA synthesis employing the Super-Script double-stranded cDNA synthesis kit (Superscript Choice System, Life Technologies, Gaithersburg, MD) with the T7-(dT) 24 primer. In vitro transcription was performed using the Enzo-IVT kit (Enzo BioArray High Yield RNA Transcript Labelling Kit, Enzo Diagnostics, Farmingdale, New York, USA).…”

Section: Preparation Of Target Crna For Microarraysmentioning

confidence: 99%

Whole genome expression profiling of the medial and lateral substantia nigra in Parkinson’s disease

et al. 2006

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We have used brain tissue from clinically well-documented and neuropathologically confirmed cases of sporadic Parkinson's disease to establish the transcriptomic expression profile of the medial and lateral substantia nigra. In addition, the superior frontal cortex was analyzed in a subset of the same cases. DNA oligonucleotide microarrays were employed, which provide whole human genome coverage. A total of 570 genes were found to be differentially regulated at a high level of significance. A large number of differentially regulated expressed sequence tags were also identified. Levels of mRNA sequences encoded by genes of key interest were validated by means of quantitative realtime polymerase chain reaction (PCR). Comparing three different normalization procedures, results based on the recently published GeneChip Robust Multi Array algorithm were found to be the most accurate predictor of realtime PCR results. Several new candidate genes which map to PARK loci are reported. In addition, the DNAJ family of chaperones is discussed in the context of Parkinson's disease pathogenesis.

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Expression Profiling of Substantia Nigra in Parkinson Disease, Progressive Supranuclear Palsy, and Frontotemporal Dementia With Parkinsonism

Cited by 153 publications

References 23 publications

Analysis of alpha-synuclein, dopamine and parkin pathways in neuropathologically confirmed parkinsonian nigra

Analysis of alpha-synuclein, dopamine and parkin pathways in neuropathologically confirmed parkinsonian nigra

Heat shock proteins in neurodegenerative disorders and aging

Whole genome expression profiling of the medial and lateral substantia nigra in Parkinson’s disease

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