The role of PIMT in Alzheimer's disease pathogenesis: A novel hypothesis.
Alzheimer's disease
DNA hypomethylation
L-isoaspartyl methyltransferase
amyloid beta plaques
one-carbon metabolism
Journal
Alzheimer's & dementia : the journal of the Alzheimer's Association
ISSN: 1552-5279
Titre abrégé: Alzheimers Dement
Pays: United States
ID NLM: 101231978
Informations de publication
Date de publication:
11 2023
11 2023
Historique:
received:
09
03
2023
accepted:
11
04
2023
medline:
16
11
2023
pubmed:
9
5
2023
entrez:
8
5
2023
Statut:
ppublish
Résumé
There are multiple theories of Alzheimer's disease pathogenesis. One major theory is that oxidation of amyloid beta (Aβ) promotes plaque deposition that directly contributes to pathology. A competing theory is that hypomethylation of DNA (due to altered one carbon metabolism) results in pathology through altered gene regulation. Herein, we propose a novel hypothesis involving L-isoaspartyl methyltransferase (PIMT) that unifies the Aβ and DNA hypomethylation hypotheses into a single model. Importantly, the proposed model allows bidirectional regulation of Aβ oxidation and DNA hypomethylation. The proposed hypothesis does not exclude simultaneous contributions by other mechanisms (e.g., neurofibrillary tangles). The new hypothesis is formulated to encompass oxidative stress, fibrillation, DNA hypomethylation, and metabolic perturbations in one carbon metabolism (i.e., methionine and folate cycles). In addition, deductive predictions of the hypothesis are presented both to guide empirical testing of the hypothesis and to provide candidate strategies for therapeutic intervention and/or nutritional modification. HIGHLIGHTS: PIMT repairs L-isoaspartyl groups on amyloid beta and decreases fibrillation. SAM is a common methyl donor for PIMT and DNA methyltransferases. Increased PIMT activity competes with DNA methylation and vice versa. The PIMT hypothesis bridges a gap between plaque and DNA methylation hypotheses.
Substances chimiques
Amyloid beta-Peptides
0
Protein D-Aspartate-L-Isoaspartate Methyltransferase
EC 2.1.1.77
DNA
9007-49-2
Carbon
7440-44-0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
5296-5302Informations de copyright
© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.
Références
Prevention CfDCa. Alzheimer's Disease and Related Dementias. CDC. 2022.
Oney M, White L, Coe NB. Out-of-pocket costs attributable to dementia: a longitudinal analysis. J Am Geriatr Soc. 2022;70:1538-1545.
Guo T, Zhang D, Zeng Y, Huang TY, Xu H, Zhao Y. Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer's disease. Mol Neurodegener. 2020;15:40.
Chen F, Wang N, He X. Identification of differential genes of DNA methylation associated with Alzheimer's disease based on integrated bioinformatics and its diagnostic significance. Front Aging Neurosci. 2022;14:884367.
Ducker GS, Rabinowitz JD. One-carbon metabolism in health and disease. Cell Metab. 2017;25:27-42.
Selhub J. Folate, vitamin B12 and vitamin B6 and one carbon metabolism. J Nutr Health Aging. 2002;6:39-42.
Teruya T, Chen YJ, Kondoh H, Fukuji Y, Yanagida M. Whole-blood metabolomics of dementia patients reveal classes of disease-linked metabolites. Proc Natl Acad Sci U S A. 2021;118:e2022857118.
Bottiglieri T, Godfrey P, Flynn T, Carney MW, Toone BK, Reynolds EH. Cerebrospinal fluid S-adenosylmethionine in depression and dementia: effects of treatment with parenteral and oral S-adenosylmethionine. J Neurol Neurosurg Psychiatry. 1990;53:1096-1098.
Morrison LD, Smith DD, Kish SJ. Brain S-adenosylmethionine levels are severely decreased in Alzheimer's disease. J Neurochem. 1996;67:1328-1331.
Hooshmand B, Refsum H, Smith AD, et al. Association of methionine to homocysteine status with brain magnetic resonance imaging measures and risk of dementia. JAMA Psychiatry. 2019;76:1198-1205.
Guiraud SP, Montoliu I, Da Silva L, et al. High-throughput and simultaneous quantitative analysis of homocysteine-methionine cycle metabolites and co-factors in blood plasma and cerebrospinal fluid by isotope dilution LC-MS/MS. Anal Bioanal Chem. 2017;409:295-305.
Zhang X, Bao G, Liu D, et al. The association between folate and Alzheimer's disease: a systematic review and meta-analysis. Front Neurosci. 2021;15:661198.
Lauer AA, Grimm HS, Apel B, et al. Mechanistic link between vitamin B12 and Alzheimer's disease. Biomolecules. 2022;12:12.
Smith AD, Refsum H. Homocysteine - from disease biomarker to disease prevention. J Intern Med. 2021;290:826-854.
Smith AD, Refsum H, Bottiglieri T, et al. Homocysteine and dementia: an international consensus statement. J Alzheimers Dis. 2018;62:561-570.
Smith AD, Warren MJ, Refsum H. Vitamin B(12). Adv Food Nutr Res. 2018;83:215-279.
Chen H, Liu S, Ge B, et al. Effects of folic acid and vitamin b12 supplementation on cognitive impairment and inflammation in patients with Alzheimer's disease: a randomized, single-blinded, placebo-controlled trial. J Prev Alzheimers Dis. 2021;8:249-256.
Rai V. Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and Alzheimer disease risk: a meta-analysis. Mol Neurobiol. 2017;54:1173-1186.
Shimizu T, Matsuoka Y, Shirasawa T. Biological significance of isoaspartate and its repair system. Biol Pharm Bull. 2005;28:1590-1596.
Schaffert LN, Carter WG. Do post-translational modifications influence protein aggregation in neurodegenerative diseases: a systematic review. Brain Sci. 2020;10:232.
Moro ML, Phillips AS, Gaimster K, et al. Pyroglutamate and isoaspartate modified Amyloid-Beta in ageing and Alzheimer's disease. Acta Neuropathol Commun. 2018;6:3.
Chatterjee T, Das G, Chatterjee BK, Dhar J, Ghosh S, Chakrabarti P. The role of isoaspartate in fibrillation and its prevention by Protein-L-isoaspartyl methyltransferase. Biochim Biophys Acta Gen Subj. 2020;1864:129500.
Gnoth K, Piechotta A, Kleinschmidt M, et al. Targeting isoaspartate-modified Abeta rescues behavioral deficits in transgenic mice with Alzheimer's disease-like pathology. Alzheimers Res Ther. 2020;12:149.
Shimizu T, Fukuda H, Murayama S, Izumiyama N, Shirasawa T. Isoaspartate formation at position 23 of amyloid beta peptide enhanced fibril formation and deposited onto senile plaques and vascular amyloids in Alzheimer's disease. J Neurosci Res. 2002;70:451-461.
Warmack RA, Boyer DR, Zee CT, et al. Structure of amyloid-beta (20-34) with Alzheimer's-associated isomerization at Asp23 reveals a distinct protofilament interface. Nat Commun. 2019;10:3357.
Tomidokoro Y, Rostagno A, Neubert TA, et al. Iowa variant of familial Alzheimer's disease: accumulation of posttranslationally modified AbetaD23N in parenchymal and cerebrovascular amyloid deposits. Am J Pathol. 2010;176:1841-1854.
Geiger T, Clarke S. Deamidation, isomerization, and racemization at asparaginyl and aspartyl residues in peptides. Succinimide-linked reactions that contribute to protein degradation. J Biol Chem. 1987;262:785-794.
Desrosiers RR, Fanelus I. Damaged proteins bearing L-isoaspartyl residues and aging: a dynamic equilibrium between generation of isomerized forms and repair by PIMT. Curr Aging Sci. 2011;4:8-18.
Jung G, Ryu J, Heo J, Lee SJ, Cho JY, Hong S. Protein L-isoaspartyl O-methyltransferase inhibits amyloid beta fibrillogenesis in vitro. Pharmazie. 2011;66:529-534.
Kim E, Lowenson JD, Clarke S, Young SG. Phenotypic analysis of seizure-prone mice lacking L-isoaspartate (D-aspartate) O-methyltransferase. J Biol Chem. 1999;274:20671-20678.
Yamamoto A, Takagi H, Kitamura D, et al. Deficiency in protein L-isoaspartyl methyltransferase results in a fatal progressive epilepsy. J Neurosci. 1998;18:2063-2074.
Zimmer-Bensch G, Zempel H. DNA Methylation in genetic and sporadic forms of neurodegeneration: lessons from Alzheimer's, related tauopathies and genetic tauopathies. Cells. 2021;10:3064.
D'Alessandro A, Hay A, Dzieciatkowska M, et al. Protein-L-isoaspartate O-methyltransferase is required for in vivo control of oxidative damage in red blood cells. Haematologica. 2021;106:2726-2739.
Gasparoni G, Bultmann S, Lutsik P, et al. DNA methylation analysis on purified neurons and glia dissects age and Alzheimer's disease-specific changes in the human cortex. Epigenetics Chromatin. 2018;11:41.
Morris MC, Evans DA, Bienias JL, et al. Dietary folate and vitamin B12 intake and cognitive decline among community-dwelling older persons. Arch Neurol. 2005;62:641-645.
Morris MS, Jacques PF, Rosenberg IH, Selhub J. Folate and vitamin B-12 status in relation to anemia, macrocytosis, and cognitive impairment in older Americans in the age of folic acid fortification. Am J Clin Nutr. 2007;85:193-200.
Selhub J, Rosenberg IH. Excessive folic acid intake and relation to adverse health outcome. Biochimie. 2016;126:71-78.
Henry CJ, Nemkov T, Casás-Selves M, et al. Folate dietary insufficiency and folic acid supplementation similarly impair metabolism and compromise hematopoiesis. Haematologica. 2017;102:1985-1994.
Obeid R, Kasoha M, Knapp JP, et al. Folate and methylation status in relation to phosphorylated tau protein(181P) and beta-amyloid(1-42) in cerebrospinal fluid. Clin Chem. 2007;53:1129-1136.
McCaddon A, Hudson PR. Methylation and phosphorylation: a tangled relationship? Clin Chem. 2007;53:999-1000.
Hooshmand B, Polvikoski T, Kivipelto M, et al. Plasma homocysteine, Alzheimer and cerebrovascular pathology: a population-based autopsy study. Brain. 2013;136:2707-2716.
Nemkov T, Reisz JA, Xia Y, Zimring JC, D'Alessandro A. Red blood cells as an organ? How deep omics characterization of the most abundant cell in the human body highlights other systemic metabolic functions beyond oxygen transport. Expert Rev Proteomics. 2018;15:855-864.
Galletti P, Ingrosso D, Nappi A, Gragnaniello V, Iolascon A, Pinto L. Increased methyl esterification of membrane proteins in aged red-blood cells. Preferential esterification of ankyrin and band-4.1 cytoskeletal proteins. Eur J Biochem. 1983;135:25-31.
Reisz JA, Nemkov T, Dzieciatkowska M, et al. Methylation of protein aspartates and deamidated asparagines as a function of blood bank storage and oxidative stress in human red blood cells. Transfusion. 2018;58:2978-2991.
Perna AF, Ingrosso D, De Santo NG, Galletti P, Zappia V. Mechanism of erythrocyte accumulation of methylation inhibitor S-adenosylhomocysteine in uremia. Kidney Int. 1995;47:247-253.
Naumova OY, Lipschutz R, Rychkov SY, Zhukova OV, Grigorenko EL. DNA methylation alterations in blood cells of toddlers with down syndrome. Genes (Basel). 2021:12.
Ingrosso D, D'Angelo S, Perna AF, et al. Increased membrane-protein methylation in hereditary spherocytosis. A marker of cytoskeletal disarray. Eur J Biochem. 1995;228:894-898.
Galletti P, De Bonis ML, Sorrentino A, et al>. Accumulation of altered aspartyl residues in erythrocyte proteins from patients with down's syndrome. FEBS J. 2007;274:5263-5277.
Wang J, Guo C, Meng Z, et al. Testing the link between isoaspartate and Alzheimer's disease etiology. Alzheimers Dement. 2023;19(4):1491-1502.
Kitada M, Ogura Y, Monno I, Xu J, Koya D. Effect of methionine restriction on aging: its relationship to oxidative stress. Biomedicines. 2021;9:130.
Lee BC, Kaya A, Gladyshev VN. Methionine restriction and life-span control. Ann N Y Acad Sci. 2016;1363:116-124.
Sanderson SM, Gao X, Dai Z, Locasale JW. Methionine metabolism in health and cancer: a nexus of diet and precision medicine. Nat Rev Cancer. 2019;19:625-637.
Mahmoud AM, Ali MM. Methyl donor micronutrients that modify DNA methylation and cancer outcome. Nutrients. 2019;11:608.
Kanno K, Wu MK, Scapa EF, Roderick SL, Cohen DE. Structure and function of phosphatidylcholine transfer protein (PC-TP)/StarD2. Biochim Biophys Acta. 2007;1771:654-662.