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TIGAR inclusion pathology is specific for Lewy body diseases.
Brain Res. 2019 03 01; 1706:218-223.BR

Abstract

BACKGROUND

We previously reported up-regulation of tigarb (the zebrafish orthologue of human TIGAR, TP53 - Induced Glycolysis and Apoptosis Regulator) in a zebrafish pink1-/- model of Parkinson's disease (PD). Genetic inactivation of tigarb led to the rescue of dopaminergic neurons and mitochondrial function in pink-/- zebrafish. The aim of this study was to determine the relevance of TIGAR for human PD, investigate its disease specificity and identify relevant upstream and downstream mechanisms.

MATERIALS AND METHODS

TIGAR Immunohistochemistry, using a range of antibodies, was undertaken for detailed assessment of TIGAR in formalin-fixed, paraffin-embedded tissue from post mortem brains of PD patients and other neurodegenerative disorders (n = 10 controls, 10 PD cases, 10 dementia with Lewy bodies, 5 motor neurone disease (MND), 3 multiple system atrophy (MSA)) and complemented by immunohistochemistry for p53, hexokinase I (HK-I) and hexokinase II (HK-II; n = 4 control, 4 PD, and 4 dementia with Lewy bodies).

RESULTS

TIGAR was detected in Lewy bodies and Lewy neurites in the substantia nigra of sporadic PD and Dementia with Lewy bodies (DLB) patients. Staining of adjacent sections and double staining confirmed the presence of TIGAR alongside alpha-synuclein in these LB and neurites. In contrast, TIGAR-positive aggregates were not seen in cortical Lewy bodies. TIGAR protein was also absent in both TDP-43-positive inclusions in MND and glial cytoplasmic inclusions in MSA. Subsequent investigation of the TIGAR-upstream regulator p53 and the downstream targets HK-I and HK-II in PD brains suggested a possible mild increase in HK-I.

CONCLUSIONS

TIGAR protein, is present in SN Lewy bodies of both sporadic PD and DLB. The absence of TIGAR protein in the pathological inclusions of MND or MSA suggests disease specificity and further raises the possibility that TIGAR may be involved in PD pathogenesis.

Authors+Show Affiliations

Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK.Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK.Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK.Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK.Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK.Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK.Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK. Electronic address: robin.highley@sheffield.ac.uk.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30267647

Citation

López, Karla L Robles, et al. "TIGAR Inclusion Pathology Is Specific for Lewy Body Diseases." Brain Research, vol. 1706, 2019, pp. 218-223.
López KLR, Simpson JE, Watson LC, et al. TIGAR inclusion pathology is specific for Lewy body diseases. Brain Res. 2019;1706:218-223.
López, K. L. R., Simpson, J. E., Watson, L. C., Mortiboys, H., Hautbergue, G. M., Bandmann, O., & Highley, J. R. (2019). TIGAR inclusion pathology is specific for Lewy body diseases. Brain Research, 1706, 218-223. https://doi.org/10.1016/j.brainres.2018.09.032
López KLR, et al. TIGAR Inclusion Pathology Is Specific for Lewy Body Diseases. Brain Res. 2019 03 1;1706:218-223. PubMed PMID: 30267647.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - TIGAR inclusion pathology is specific for Lewy body diseases. AU - López,Karla L Robles, AU - Simpson,Julie E, AU - Watson,Lisa C, AU - Mortiboys,Heather, AU - Hautbergue,Guillaume M, AU - Bandmann,Oliver, AU - Highley,J Robin, Y1 - 2018/09/26/ PY - 2018/05/01/received PY - 2018/09/20/revised PY - 2018/09/23/accepted PY - 2018/9/30/pubmed PY - 2020/5/30/medline PY - 2018/9/30/entrez KW - Alpha-synuclein KW - Dementia with Lewy bodies KW - Lewy body KW - Parkinson’s disease KW - Substantia nigra KW - TIGAR SP - 218 EP - 223 JF - Brain research JO - Brain Res VL - 1706 N2 - BACKGROUND: We previously reported up-regulation of tigarb (the zebrafish orthologue of human TIGAR, TP53 - Induced Glycolysis and Apoptosis Regulator) in a zebrafish pink1-/- model of Parkinson's disease (PD). Genetic inactivation of tigarb led to the rescue of dopaminergic neurons and mitochondrial function in pink-/- zebrafish. The aim of this study was to determine the relevance of TIGAR for human PD, investigate its disease specificity and identify relevant upstream and downstream mechanisms. MATERIALS AND METHODS: TIGAR Immunohistochemistry, using a range of antibodies, was undertaken for detailed assessment of TIGAR in formalin-fixed, paraffin-embedded tissue from post mortem brains of PD patients and other neurodegenerative disorders (n = 10 controls, 10 PD cases, 10 dementia with Lewy bodies, 5 motor neurone disease (MND), 3 multiple system atrophy (MSA)) and complemented by immunohistochemistry for p53, hexokinase I (HK-I) and hexokinase II (HK-II; n = 4 control, 4 PD, and 4 dementia with Lewy bodies). RESULTS: TIGAR was detected in Lewy bodies and Lewy neurites in the substantia nigra of sporadic PD and Dementia with Lewy bodies (DLB) patients. Staining of adjacent sections and double staining confirmed the presence of TIGAR alongside alpha-synuclein in these LB and neurites. In contrast, TIGAR-positive aggregates were not seen in cortical Lewy bodies. TIGAR protein was also absent in both TDP-43-positive inclusions in MND and glial cytoplasmic inclusions in MSA. Subsequent investigation of the TIGAR-upstream regulator p53 and the downstream targets HK-I and HK-II in PD brains suggested a possible mild increase in HK-I. CONCLUSIONS: TIGAR protein, is present in SN Lewy bodies of both sporadic PD and DLB. The absence of TIGAR protein in the pathological inclusions of MND or MSA suggests disease specificity and further raises the possibility that TIGAR may be involved in PD pathogenesis. SN - 1872-6240 UR - https://www.unboundmedicine.com/medline/citation/30267647/TIGAR_inclusion_pathology_is_specific_for_Lewy_body_diseases_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-8993(18)30497-9 DB - PRIME DP - Unbound Medicine ER -