Isopentenyl diphosphate isomerase, a cholesterol synthesizing enzyme, is localized in <scp>L</scp>ewy bodies

Nakamura, Keiko; Mori, Fumiaki; Tanji, Kunikazu; Miki, Yasuo; Yamada, Masahito; Kakita, Akiyoshi; Takahashi, Hitoshi; Utsumi, Jun; Sasaki, Hidenao; Wakabayashi, Keiji

doi:10.1111/neup.12204

Cited by 36 publications

(24 citation statements)

References 31 publications

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“…Furthermore, TIGAR incorporation into Lewy bodies was only seen in brainstem but not cortical Lewy bodies. This phenomenon has also been seen with respect to isopentenyl diphosphate isomerase (Nakamura et al, 2015),. This is unusual, as most Lewy body protein components are present in both brainstem and cortical Lewy bodies (e.g, alpha-synuclein , MAP-5 (Gai et al, 1996), HDAC6 , Parkin , cyclin dependent kinase 5 , synphilin-1 .…”

Section: Within Individual Brains We Found Variable Expression Of Tisupporting

confidence: 54%

TIGAR inclusion pathology is specific for Lewy body diseases

et al. 2019

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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 confirmed the presence of TIGAR alongside alphasynuclein 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 ID Sex Diagnosis Age (years) P2/10 F sPD 82 P54/11 M sPD 80 P89/10 M sPD 77

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Section: Within Individual Brains We Found Variable Expression Of Tisupporting

confidence: 54%

TIGAR inclusion pathology is specific for Lewy body diseases

et al. 2019

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“…In PD patients, the cholesterol-synthesizing enzymes isopentenyl diphosphate isomerases 1 and 2 have been observed in LB from the SN of PD patients [518]. The natural cholesterol intermediate squalene seems to prevent toxicity in the striatum of 6-OHDA-treated mice [519], whereas α-synuclein accumulation enhances squalene production [242], which could be a cellular response to oxidative damage.…”

Section: Sterolsmentioning

confidence: 99%

The Role of Lipids in Parkinson’s Disease

Xicoy

Wieringa

Martens

2019

Cells

181

161

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Parkinson’s disease (PD) is a neurodegenerative disease characterized by a progressive loss of dopaminergic neurons from the nigrostriatal pathway, formation of Lewy bodies, and microgliosis. During the past decades multiple cellular pathways have been associated with PD pathology (i.e., oxidative stress, endosomal-lysosomal dysfunction, endoplasmic reticulum stress, and immune response), yet disease-modifying treatments are not available. We have recently used genetic data from familial and sporadic cases in an unbiased approach to build a molecular landscape for PD, revealing lipids as central players in this disease. Here we extensively review the current knowledge concerning the involvement of various subclasses of fatty acyls, glycerolipids, glycerophospholipids, sphingolipids, sterols, and lipoproteins in PD pathogenesis. Our review corroborates a central role for most lipid classes, but the available information is fragmented, not always reproducible, and sometimes differs by sex, age or PD etiology of the patients. This hinders drawing firm conclusions about causal or associative effects of dietary lipids or defects in specific steps of lipid metabolism in PD. Future technological advances in lipidomics and additional systematic studies on lipid species from PD patient material may improve this situation and lead to a better appreciation of the significance of lipids for this devastating disease.

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“…It has been reported that cholesterol biosynthesis is decreased in fibroblasts from patients with PD owing to reduced β-Hydroxy β-methylglutaryl-CoA (HMG-CoA) reductase activity [81]. In addition, isopentenyl diphosphate isomerase, a cholesterol-synthesizing enzyme, is localized in Lewy bodies, proposing that cholesterol metabolites may play a role in the aggregation of α-synuclein, enhancing Lewy body formation [82].…”

Section: Alterations Of Cholesterol Metabolism In Pdmentioning

confidence: 99%

Cholesterol Metabolism in the Brain and Its Association with Parkinson’s Disease

2019

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Parkinson’s disease (PD) is the second most progressive neurodegenerative disorder of the aging population after Alzheimer’s disease (AD). Defects in the lysosomal systems and mitochondria have been suspected to cause the pathogenesis of PD. Nevertheless, the pathogenesis of PD remains obscure. Abnormal cholesterol metabolism is linked to numerous disorders, including atherosclerosis. The brain contains the highest level of cholesterol in the body and abnormal cholesterol metabolism links also many neurodegenerative disorders such as AD, PD, Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS). The blood brain barrier effectively prevents uptake of lipoprotein-bound cholesterol from blood circulation. Accordingly, cholesterol level in the brain is independent from that in peripheral tissues. Because cholesterol metabolism in both peripheral tissue and the brain are quite different, cholesterol metabolism associated with neurodegeneration should be examined separately from that in peripheral tissues. Here, we review and compare cholesterol metabolism in the brain and peripheral tissues. Furthermore, the relationship between alterations in cholesterol metabolism and PD pathogenesis is reviewed.

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Isopentenyl diphosphate isomerase, a cholesterol synthesizing enzyme, is localized in Lewy bodies

Cited by 36 publications

References 31 publications

TIGAR inclusion pathology is specific for Lewy body diseases

TIGAR inclusion pathology is specific for Lewy body diseases

The Role of Lipids in Parkinson’s Disease

Cholesterol Metabolism in the Brain and Its Association with Parkinson’s Disease

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