Reduction of fetuin-A levels contributes to impairment of Purkinje cells in cerebella of patients with Parkinson’s disease
1
조회
0
다운로드
0
인용
0
참고문헌
키워드
초록
Phenotypic features such as ataxia and loss of motor function,which are characteristics of Parkinson’s disease (PD), are expectedto be very closely related to cerebellum function. However, fewstudies have reported the function of the cerebellum. Since thecerebellum, like the cerebrum, is known to undergo functionaland morphological changes due to neuroinflammatory processes,elucidating key functional factors that regulate neuroinflammationin the cerebellum can be a beneficial therapeutic approach. Therefore, we employed PD patients and MPTP-induced PDmouse model to find cytokines involved in cerebellar neuroinflammationin PD and to examine changes in cell function byregulating related genes. Along with the establishment of a PDmouse model, abnormal shapes such as arrangement and numberof Purkinje cells in the cerebellum were confirmed based onhistological finding, consistent with those of cerebellums ofPD patients. As a result of proteome profiling for neuroinflammationusing PD mouse cerebellar tissues, fetuin-A, a type ofcytokine, was found to be significantly reduced in Purkinje cells. To further elucidate the function of fetuin-A, neurons isolatedfrom cerebellums of embryos (E18) were treated with fetuin-AsiRNA. We uncovered that not only the population of neuronalcells, but also their morphological appearances were significantlydifferent. In this study, we found a functional genecalled fetuin-A in the PD model’s cerebellum, which was closelyrelated to the role of cerebellar Purkinje cells of mouse andhuman PD. In conclusion, morphological abnormalities of Purkinjecells in PD mice and patients have a close relationshipwith a decrease of fetuin-A, suggesting that diagnosis and treatmentof cerebellar functions of PD patients might be possiblethrough regulation of fetuin-A.
Abstract
Phenotypic features such as ataxia and loss of motor function,which are characteristics of Parkinson’s disease (PD), are expectedto be very closely related to cerebellum function. However, fewstudies have reported the function of the cerebellum. Since thecerebellum, like the cerebrum, is known to undergo functionaland morphological changes due to neuroinflammatory processes,elucidating key functional factors that regulate neuroinflammationin the cerebellum can be a beneficial therapeutic approach. Therefore, we employed PD patients and MPTP-induced PDmouse model to find cytokines involved in cerebellar neuroinflammationin PD and to examine changes in cell function byregulating related genes. Along with the establishment of a PDmouse model, abnormal shapes such as arrangement and numberof Purkinje cells in the cerebellum were confirmed based onhistological finding, consistent with those of cerebellums ofPD patients. As a result of proteome profiling for neuroinflammationusing PD mouse cerebellar tissues, fetuin-A, a type ofcytokine, was found to be significantly reduced in Purkinje cells. To further elucidate the function of fetuin-A, neurons isolatedfrom cerebellums of embryos (E18) were treated with fetuin-AsiRNA. We uncovered that not only the population of neuronalcells, but also their morphological appearances were significantlydifferent. In this study, we found a functional genecalled fetuin-A in the PD model’s cerebellum, which was closelyrelated to the role of cerebellar Purkinje cells of mouse andhuman PD. In conclusion, morphological abnormalities of Purkinjecells in PD mice and patients have a close relationshipwith a decrease of fetuin-A, suggesting that diagnosis and treatmentof cerebellar functions of PD patients might be possiblethrough regulation of fetuin-A.
참고문헌 (28)
- Wu T, "The cerebellum in Parkinson’s disease", Brain, 136, pp.696~709 (2013)
- Dissanayaka NN, "Anxiety disorders in Parkinson’s disease : prevalence and risk factors", Mov Disord, 25, pp.838~845 (2010)
- Reijnders JS, "A systematic review of prevalence studies of depression in Parkinson’s disease", Mov Disord, 23, pp.183~189 (2008)
- Riedel O, "Frequency of dementia, depression, and other neuropsychiatric symptoms in 1, 449 outpatients with Parkinson’s disease", J Neurol, 257, pp.1073~1082 (2010)
- Hornykiewicz O, "The discovery of dopamine deficiency in the parkinsonian brain", J Neural Transm Suppl, pp.9~15 (2006)
- Ma X, "Cerebellar atrophy in different subtypes of Parkinson’s disease", J Neurol Sci, 392, pp.105~112 (2018)
- Mirdamadi JL, "Cerebellar role in Parkinson’s disease", J Neurophysiol, 116, pp.917~919 (2016)
- Compton J, "HRT and its effect on normal ageing of the brain and dementia", Br J Clin Pharmacol, 52, pp.647~653 (2001)
- Melov S, "Modeling mitochondrial function in aging neurons", Trends Neurosci, 27, pp.601~606 (2004)
- Nguyen MD, "Innate immunity : the missing link in neuroprotection and neurodegeneration?", Nat Rev Neurosci, 3, pp.216~227 (2002)
- Di Benedetto S, "Contribution of neuroinflammation and immunity to brain aging and the mitigating effects of physical and cognitive interventions", Neurosci Biobehav Rev, 75, pp.114~128 (2017)
- Heneka MT, "Innate immune activation in neurodegenerative disease", Nat Rev Immunol, 14, pp.463~477 (2014)
- Heneka MT, "Inflammasome signalling in brain function and neurodegenerative disease", Nat Rev Neurosci, 19, pp.610~621 (2018)
- Siegel-Axel DI, "Fetuin-A influences vascular cell growth and production of proinflammatory and angiogenic proteins by human perivascular fat cells", Diabetologia, 57, pp.1057~1066 (2014)
- Chekol Abebe E, "The structure, biosynthesis, and biological roles of fetuin-A : a review", Front Cell Dev Biol, 10, pp.945287~ (2022)
- Trepanowski J, "Fetuin-A : a novel link between obesity and related complications", Int J Obes(Lond), 39, pp.734~741 (2015)
- Wojtysiak-Duma B, "Serum fetuin-A levels in patients with type 2 diabetes mellitus", Ann UMCS Sect, 23, pp.93~99 (2010)
- Wang H, "Peripheral administration of fetuin-A attenuates early cerebral ischemic injury in rats", J Cereb Blood Flow Metab, 30, pp.493~504 (2010)
- Lofrumento DD, "MPTP-induced neuroinflammation increases the expression of pro-inflammatory cytokines and their receptors in mouse brain", Neuroimmunomodulation, 18, pp.79~88 (2011)
- Vignola C, "MPTP-induced changes in the monkey cerebellum-immunohistochemistry of calcium-binding and cytoskeletal proteins", Neurodegeneration, 3, pp.25~31 (1994)
- Heman P, "Nigral degeneration correlates with persistent activation of cerebellar Purkinje cells in MPTP-treated monkeys", Histol Histopathol, 27, pp.89~94 (2012)
- Hirano T, "Purkinje neurons : development, morphology, and function", Cerebellum, 17, pp.699~700 (2018)
- Hashimoto M, "Motor and non-motor projections from the cerebellum to rostrocaudally distinct sectors of the dorsal premotor cortex in macaques", Eur J Neurosci, 31, pp.1402~1413 (2010)
- Carecchio M, "The role of osteopontin in neurodegenerative diseases", J Alzheimers Dis, 25, pp.179~185 (2011)
- Gellhaar S, "Myeloperoxidase-immunoreactive cells are significantly increased in brain areas affected by neurodegeneration in Parkinson’s and Alzheimer’s disease", Cell Tissue Res, 369, pp.445~454 (2017)
- Chekol Abebe E, "The structure, biosynthesis, and biological roles of fetuin-A : a review", Front Cell Dev Biol, 10, pp.945287~ (2022)
- Heinen MC, "Fetuin-A protein distribution in mature inflamed and ischemic brain tissue", PLoS One, 13, pp.e0206597~ (2018)
- Paxinos G, "Paxinos and Franklin’s the mouse brain in stereotaxic coordinates" (2019), Academic press