Effect of α-mangostin on amyotrophic lateral sclerosis and its mechanism

doi:10.3969/j.issn.1674-8115.2022.09.013

Abstract

Abstract:

Objective ·To study the effect of α-mangostin (AM) on the superoxide dismutase 1 (SOD1) mutant amyotrophic lateral sclerosis (ALS) and the possible mechanism. Methods ·The ATP level in the microglia was measured by kits to investigate the effect of AM on the energy balance in the SOD1 aggregates-treated microglia (SOD1-ALS model microglia). Western blotting was used to detect the activation levels of AMP-activated protein kinase (AMPK) and the key molecules in its metabolic regulation pathway including liver kinase B1 and PPARγ coactivator 1α, in order to explore the regulatory role of AM on AMPK pathway in the disease-associated microglia. The ATP level was also detected after AMPK activation being inhibited by compound C to explore the role of AMPK in the regulation of energy balance by AM in the SOD1-ALS microglia. The microglial uptake and degradation of SOD1 aggregates was detected by using ELISA with or without inhibition of AMPK activation, to explore the role of AMPK-mediated energy regulation in AM regulating SOD1 clearance in the disease-associated microglia. Western blotting and immunofluorescence were used to study the effect of AM on microglial autophagy and the role of autophagy in AM regulating the degradation of SOD1 in the microglia. AM-encapsulated nanoparticles (NPAMs) were prepared to realize the in vivo treatment of AM. NPAMs were injected into the SOD1*G93A ALS model mice through the caudal vein for 30 d, once a day. SOD1 aggregates were detected by immunohistochemistry in the lumbar spinal cords of the ALS mice. Neuronal damage and loss were measured by using Nissl staining and anti-NeuN immunohistochemistry. Motor ability of the ALS mice was evaluated by rotarod test and hindlimb clasping test. Disease progress of the ALS mice was evaluated by recording body mass and survival time. Results ·AM increased the ATP level in the diseased-associated microglia and enhanced microglial phagocytosis and autophagy-mediated degradation of SOD1 aggregates. While inhibiting AMPK pathway abolished these effects of AM, NPAM reduced SOD1 aggregates in the lumbar spinal cord of the SOD1*G93A ALS model mice, and reduced the neuron damage and loss. NPAM also alleviated the body mass loss and the damaged motor ability of the ALS mice. Conclusion ·AM enhances microglial clearance of SOD1 aggregates through AMPK-mediated recovery of energy balance, and thus alleviates the neuropathological changes and symptoms in ALS mice.

Key words: amyotrophic lateral sclerosis (ALS), α-mangostin (AM), microglia, superoxide dismutase 1 (SOD1), energy balance, AMP activated protein kinase (AMPK)

CLC Number:

R966

WANG Dayuan, XU Jianrong, JIANG Gan, SONG Qingxiang, CHEN Jun, SONG Huahua, GU Xiao, GAO Xiaoling. Effect of α-mangostin on amyotrophic lateral sclerosis and its mechanism[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2022, 42(9): 1265-1274.

Figures/Tables 3

TrendMD

References 35

1	HARDIMAN O, VAN DEN BERG L H, KIERNAN M C. Clinical diagnosis and management of amyotrophic lateral sclerosis[J]. Nat Rev Neurol, 2011, 7(11): 639-649.
2	CHIÒ A, MAZZINI L, MORA G. Disease-modifying therapies in amyotrophic lateral sclerosis[J]. Neuropharmacology, 2020, 167: 107986.
3	VAN ZUNDERT B, BROWN R H Jr. Silencing strategies for therapy of SOD1-mediated ALS[J]. Neurosci Lett, 2017, 636: 32-39.
4	ABATI E, BRESOLIN N, COMI G, et al. Silence superoxide dismutase 1 (SOD1): a promising therapeutic target for amyotrophic lateral sclerosis (ALS)[J]. Expert Opin Ther Targets, 2020, 24(4): 295-310.
5	PRASAD A, BHARATHI V, SIVALINGAM V, et al. Molecular mechanisms of TDP-43 misfolding and pathology in amyotrophic lateral sclerosis[J]. Front Mol Neurosci, 2019, 12: 25.
6	SHENG Y W, CHATTOPADHYAY M, WHITELEGGE J, et al. SOD1 aggregation and ALS: role of metallation states and disulfide status[J]. Curr Top Med Chem, 2012, 12(22): 2560-2572.
7	CHEN Y M, WANG H F, YING Z, et al. Ibudilast enhances the clearance of SOD1 and TDP-43 aggregates through TFEB-mediated autophagy and lysosomal biogenesis: the new molecular mechanism of ibudilast and its implication for neuroprotective therapy[J]. Biochem Biophys Res Commun, 2020, 526(1): 231-238.
8	HAN H H, WEI W Y, DUAN W S, et al. Autophagy-linked FYVE protein (Alfy) promotes autophagic removal of misfolded proteins involved in amyotrophic lateral sclerosis (ALS)[J]. In Vitro Cell Dev Biol Anim, 2015, 51(3): 249-263.
9	KIM Y, PARK J H, JANG J Y, et al. Characterization and Hsp104-induced artificial clearance of familial ALS-related SOD1 aggregates[J]. Biochem Biophys Res Commun, 2013, 434(3): 521-526.
10	CRISTOFANI R, CRIPPA V, RUSMINI P, et al. Inhibition of retrograde transport modulates misfolded protein accumulation and clearance in motoneuron diseases[J]. Autophagy, 2017, 13(8): 1280-1303.
11	PUTTAPARTHI K, WOJCIK C, RAJENDRAN B, et al. Aggregate formation in the spinal cord of mutant SOD1 transgenic mice is reversible and mediated by proteasomes[J]. J Neurochem, 2003, 87(4): 851-860.
12	COLONNA M, BUTOVSKY O. Microglia function in the central nervous system during health and neurodegeneration[J]. Annu Rev Immunol, 2017, 35: 441-468.
13	HENKEL J S, BEERS D R, ZHAO W H, et al. Microglia in ALS: the good, the bad, and the resting[J]. J Neuroimmune Pharmacol, 2009, 4(4): 389-398.
14	ALDANA B I. Microglia-specific metabolic changes in neurodegeneration[J]. J Mol Biol, 2019, 431(9): 1830-1842.
15	ENGL E, ATTWELL D. Non-signalling energy use in the brain[J]. J Physiol, 2015, 593(16): 3417-3429.
16	CHODARI L, DILSIZ AYTEMIR M, VAHEDI P, et al. Targeting mitochondrial biogenesis with polyphenol compounds[J]. Oxid Med Cell Longev, 2021, 2021: 4946711.
17	RAFIEI H, OMIDIAN K, BANDY B. Dietary polyphenols protect against oleic acid-induced steatosis in an in vitro model of NAFLD by modulating lipid metabolism and improving mitochondrial function[J]. Nutrients, 2019, 11(3): 541.
18	VAN DER BLIEK A M, SEDENSKY M M, MORGAN P G. Cell biology of the mitochondrion[J]. Genetics, 2017, 207(3): 843-871.
19	YAO L, GU X, SONG Q X, et al. Nanoformulated alpha-mangostin ameliorates Alzheimer's disease neuropathology by elevating LDLR expression and accelerating amyloid-β clearance[J]. J Control Release, 2016, 226: 1-14.
20	DEORA V, LEE J D, ALBORNOZ E A, et al. The microglial NLRP3 inflammasome is activated by amyotrophic lateral sclerosis proteins[J]. Glia, 2020, 68(2): 407-421.
21	GILL C, PHELAN J P, HATZIPETROS T, et al. SOD1-positive aggregate accumulation in the CNS predicts slower disease progression and increased longevity in a mutant SOD1 mouse model of ALS[J]. Sci Rep, 2019, 9(1): 6724.
22	ZHAO Z C, FU J S, LI S P, et al. Neuroprotective effects of genistein in a SOD1-G93A transgenic mouse model of amyotrophic lateral sclerosis[J]. J Neuroimmune Pharmacol, 2019, 14(4): 688-696.
23	MARTÍNEZ-MURIANA A, MANCUSO R, FRANCOS-QUIJORNA I, et al. CSF1R blockade slows the progression of amyotrophic lateral sclerosis by reducing microgliosis and invasion of macrophages into peripheral nerves[J]. Sci Rep, 2016, 6: 25663.
24	XIE M L, LIU Y U, ZHAO S Y, et al. TREM2 interacts with TDP-43 and mediates microglial neuroprotection against TDP-43-related neurodegeneration[J]. Nat Neurosci, 2022, 25(1): 26-38.
25	BONORA M, PATERGNANI S, RIMESSI A, et al. ATP synthesis and storage[J]. Purinergic Signal, 2012, 8(3): 343-357.
26	GARCIA D, SHAW R J. AMPK: mechanisms of cellular energy sensing and restoration of metabolic balance[J]. Mol Cell, 2017, 66(6): 789-800.
27	FU R Y, SHEN Q Y, XU P F, et al. Phagocytosis of microglia in the central nervous system diseases[J]. Mol Neurobiol, 2014, 49(3): 1422-1434.
28	VARSHAVSKY A. The ubiquitin system, autophagy, and regulated protein degradation[J]. Annu Rev Biochem, 2017, 86: 123-128.
29	PLAZA-ZABALA A, SIERRA-TORRE V, SIERRA A. Autophagy and microglia: novel partners in neurodegeneration and aging[J]. Int J Mol Sci, 2017, 18(3): 598.
30	KAUR S J, MCKEOWN S R, RASHID S. Mutant SOD1 mediated pathogenesis of amyotrophic lateral sclerosis[J]. Gene, 2016, 577(2): 109-118.
31	NORRIS S P, LIKANJE M F N, ANDREWS J A. Amyotrophic lateral sclerosis: update on clinical management[J]. Curr Opin Neurol, 2020, 33(5): 641-648.
32	HARDIMAN O, AL-CHALABI A, CHIO A, et al. Amyotrophic lateral sclerosis[J]. Nat Rev Dis Primers, 2017, 3: 17071.
33	LI L, BRUNNER I, HAN A R, et al. Pharmacokinetics of α‑mangostin in rats after intravenous and oral application[J]. Mol Nutr Food Res, 2011, 55(Suppl 1): S67-S74.
34	WANG D Y, GU X, MA X Y, et al. Nanopolyphenol rejuvenates microglial surveillance of multiple misfolded proteins through metabolic reprogramming[J]. Acta Pharm Sin B, 2022. DOI: https://doi.org/10.1016/j.apsb.2022.07.014.
35	BARTANUSZ V, JEZOVA D, ALAJAJIAN B, et al. The blood-spinal cord barrier: morphology and clinical implications[J]. Ann Neurol, 2011, 70(2): 194-206.

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