The role of PIMT in Alzheimer's disease pathogenesis: A novel hypothesis

Abstract

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.

U1 snRNP Biogenesis Defects in Neurodegenerative Diseases

“…Later, it was shown that the C‐terminal part of U1‐70K, a region with highly repetitive basic (Arg/Lys) and acidic (Asp/Glu) residues is sufficient to interact with tau from AD patients but not from other tauopathies [43] . Another intriguing link between Alzheimer's disease and U1 snRNP biogenesis resides in the role of Tgs1/PIMT in neurodegeneration [44] . This enzyme colocalizes with neurofibrillary tangles in AD patient brains, [45] suggesting that U1 snRNP biogenesis intermediates could also be trapped in cytoplasmic tau aggregates (Figure 2).…”

Exploring unconventional attributes of red blood cells and their potential applications in biomedicine

“…Analogously, fibrils on the RBC surface, postulated to be comprised of β-amyloid and tau isoforms, are potential biomarkers for early detection of Alzheimer’s disease ( Nirmalraj et al, 2021 ). One key phenomenon in both Alzheimer’s Disease and RBC responses to hypoxia involves protein isoaspartyl-damage arising from dehydration/deamidation-triggering oxidant challenges (e.g., to structural proteins like 4.1 and band 3 in the aging RBC; to tau protein in Alzheimer’s disease), a process that is, in part, counteracted by protein L-isoaspartyl O-methyltransferase both in RBCs and neural cells ( D’Alessandro et al, 2023b ). Blood testing to classify patients was recently described using plasma tau protein 217, potentially accurately stratifying and detecting Alzheimer’s disease in a cost-effective way ( Brum et al, 2023 ).…”

MTHFR and LC, CFS, POTS, MCAS, SIBO, EDS: Methylating the Alphabet Torrance Memorial Medical Center, Dept of Pathology

“…Hypermethylation can help drive carcinogenesis, autoimmune disease, and neurodegenerative disease 59 . Hypomethylation can also drive cancer, autoimmune disease 60 , and perhaps neurodegenerative disease as well 61 .…”