INT281878

Context Info Confidence 0.31 First Reported 2009 Last Reported 2010 Negated 1 Speculated 1 Reported most in Body Documents 35 Total Number 36 Disease Relevance 17.15 Pain Relevance 1.98

cytosol (Aco1) mitochondrion (Aco1) lyase activity (Aco1) Golgi apparatus (Aco1) endoplasmic reticulum (Aco1) RNA binding (Aco1)

Anatomy Link Frequency neurons 14 midbrain 10 neuronal 6 astrocytes 6 Aco1 (Mus musculus)

Pain Link Frequency Relevance Heat midbrain 630 99.86 addiction 35 99.36 Pain 35 98.32 Substantia nigra 35 81.52 ischemia 35 36.24 Inflammation 35 13.60 tolerance 2 5.00 Analgesic 1 5.00 Thoracotomy 1 5.00 Paracetamol 1 5.00

Disease Link Frequency Relevance Heat Death 2065 99.92 Parkinson's Disease 385 99.24 Pain 35 98.32 Drug Induced Neurotoxicity 280 98.04 Stress 421 92.04 Infection 35 91.36 Cytomegalovirus Infection 175 86.64 Sprains And Strains 70 76.36 Disease 315 73.04 Neurodegenerative Disease 140 67.12

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Anatomy

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Speculation

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Transduction with AdAcon increases aconitase expression and activity in primary midbrain cultures

Positive_regulation (increases) of Gene_expression (expression) of aconitase in midbrain associated with midbrain

1) Confidence 0.31 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2738973 Disease Relevance 0.22 Pain Relevance 0.08

In summary, since catalase can only attenuate cell death when m-aconitase is overexpressed, this suggests 1) that the excess H2O2 from m-aconitase inactivation is being released from astrocytes and injuring neighboring neurons and 2) that removal of astrocyte-derived extracellular H2O2 can prevent death.

Positive_regulation (overexpressed) of Gene_expression (overexpressed) of m-aconitase in astrocytes associated with death

2) Confidence 0.27 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2738973 Disease Relevance 0.69 Pain Relevance 0

The exacerbation of Fe2+ and H2O2 production in m-aconitase overexpressing cells suggests its role as their source.

Positive_regulation (overexpressing) of Gene_expression (overexpressing) of m-aconitase

3) Confidence 0.27 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2738973 Disease Relevance 0.38 Pain Relevance 0

Overexpression of m-aconitase was achieved by transducing cells with an adenoviral construct expressing m-aconitase cDNA and a GFP reporter (AdAcon) or with an adenoviral construct only expressing GFP (AdGFP) to control for viral-mediated effects.

Positive_regulation (Overexpression) of Gene_expression (Overexpression) of m-aconitase

4) Confidence 0.27 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2738973 Disease Relevance 0.18 Pain Relevance 0.04

More importantly, neurons from AdAcon transduced cultures revealed greater damage than AdGFP transduced cells at 500 µM PQ2+ supporting that m-aconitase overexpression exacerbates neuronal death upon oxidative inactivation.

Positive_regulation (overexpression) of Gene_expression (overexpression) of m-aconitase in neurons associated with death

5) Confidence 0.27 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2738973 Disease Relevance 0.32 Pain Relevance 0

M-aconitase was overexpressed in mature primary midbrain cultures using an adenoviral vector.

Positive_regulation (overexpressed) of Gene_expression (overexpressed) of M-aconitase in midbrain associated with midbrain

6) Confidence 0.27 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2738973 Disease Relevance 0.43 Pain Relevance 0.19

Overexpression of m-aconitase resulted in a concentration-dependent decrease of cell viability compared to GFP-only expressing cells (Fig. 5).

Positive_regulation (Overexpression) of Gene_expression (Overexpression) of m-aconitase

7) Confidence 0.27 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2738973 Disease Relevance 0.52 Pain Relevance 0

Although astrocytes were the predominant cell type to overexpress m-aconitase, the neuronal population was more susceptible to death compared to astrocytes.

Positive_regulation (overexpress) of Gene_expression (overexpress) of m-aconitase in neuronal associated with death

8) Confidence 0.27 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2738973 Disease Relevance 0.57 Pain Relevance 0.07

To confirm the role of m-aconitase versus other cellular proteins in the production of Fe2+ and H2O2, we specifically overexpressed m-aconitase.

Positive_regulation (overexpressed) of Gene_expression (overexpressed) of m-aconitase

9) Confidence 0.27 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2738973 Disease Relevance 0.17 Pain Relevance 0.07

We hypothesized that increasing the levels of m-aconitase would increase the amount of target enzyme available for oxidative inactivation leading to exacerbation of H2O2 production, Fe2+ formation and cell death.

Positive_regulation (increasing) of Gene_expression (levels) of m-aconitase associated with death

10) Confidence 0.27 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2738973 Disease Relevance 0.18 Pain Relevance 0.07

Astrocytic overexpression of m-aconitase results in neuronal death

Positive_regulation (overexpression) of Gene_expression (overexpression) of m-aconitase in neuronal associated with death

11) Confidence 0.27 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2738973 Disease Relevance 0.61 Pain Relevance 0.05

Fenton reaction) in cells expressing basal levels of m-aconitase, extracellular H2O2 was also mediating cell death in m-aconitase overexpressing cultures.

Positive_regulation (overexpressing) of Gene_expression (overexpressing) of m-aconitase associated with death

12) Confidence 0.27 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2738973 Disease Relevance 0.77 Pain Relevance 0

However, in m-aconitase overexpressing cells, either catalase or HBED was sufficient to significantly inhibit cell death (Fig. 7).

Positive_regulation (overexpressing) of Gene_expression (overexpressing) of m-aconitase associated with death

13) Confidence 0.27 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2738973 Disease Relevance 0.96 Pain Relevance 0.06

To confirm the role of m-aconitase as a source of Fenton reagents and death, we overexpressed m-aconitase using an adenoviral construct thereby increasing the target available for inactivation by ROS.

Positive_regulation (overexpressed) of Gene_expression (overexpressed) of m-aconitase associated with death

14) Confidence 0.27 Published 2009 Journal PLoS ONE Section Abstract Doc Link PMC2738973 Disease Relevance 0.69 Pain Relevance 0

To confirm the mechanism of H2O2 and Fe2+ in the death of cells overexpressing m-aconitase, we asked whether cell death could be prevented by their pharmacological removal using catalase and HBED respectively.

Positive_regulation (overexpressing) of Gene_expression (overexpressing) of m-aconitase associated with death

15) Confidence 0.27 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2738973 Disease Relevance 1.02 Pain Relevance 0.05

Co-localization of GFP fluorescence with MAP2 and GFAP performed 24 hrs after transduction with AdAcon, revealed the expression of m-aconitase largely in GFAP positive cells, suggesting that m-aconitase was predominately overexpressed in astrocytes (Fig. 8a,b).

Positive_regulation (overexpressed) of Gene_expression (overexpressed) of m-aconitase in astrocytes

16) Confidence 0.27 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2738973 Disease Relevance 0.47 Pain Relevance 0.04

generating compound PQ2+ on aconitase activity, H2O2 production, mitochondrial Fe2+ accumulation and cell death in primary midbrain cultures.

Positive_regulation (accumulation) of Gene_expression (generating) of aconitase in midbrain associated with midbrain and death

17) Confidence 0.23 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2738973 Disease Relevance 0.44 Pain Relevance 0.12

generating compound PQ2+ on aconitase activity, H2O2 production, mitochondrial Fe2+ accumulation and cell death in primary midbrain cultures.

Positive_regulation (generating) of Gene_expression (generating) of aconitase in midbrain associated with midbrain and death

18) Confidence 0.23 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2738973 Disease Relevance 0.44 Pain Relevance 0.12

Oxidative inactivation of m-aconitase overexpressing cultures resulted in exacerbation of H2O2 production, Fe2+ accumulation and increased neuronal death.

Positive_regulation (overexpressing) of Gene_expression (overexpressing) of m-aconitase in neuronal associated with death

19) Confidence 0.20 Published 2009 Journal PLoS ONE Section Abstract Doc Link PMC2738973 Disease Relevance 0.71 Pain Relevance 0

We proceeded to test whether increasing m-aconitase expression would exacerbate the release of Fenton reactants following oxidative inactivation.

Spec (whether) Positive_regulation (increasing) of Gene_expression (expression) of m-aconitase

20) Confidence 0.20 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2738973 Disease Relevance 0.06 Pain Relevance 0.11

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