Multicomponent Mendelian randomization and machine learning studies of potential drug targets for neurodegenerative diseases 2025
Chinese preprint
Neurodegenerative diseases (NDDs) remain a global health challenge. Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the main types of NDDs worldwide, and Mendelian Randomization (MR) analysis across multi-omics and the entire genome offers novel strategies for identifying potential drug targets. This study used MR and summary-based MR(SMR) analysis to explore the causal relationship between genes and NDDs. Colocalization analysis and machine learning further validated and reinforced the MR findings. The pharmacological activity of candidate drug targets was confirmed via molecular docking and Molecular dynamics. This study revealed 14 genes that were closely associated with both NDDs. Specifically, IQCE(AD), HDHD2(AD), COMMD10(AD), ALPP (AD), FXYD6 (AD), STK3 (PD), LHFPL2 (PD), and ENPP4 (PD) were identified as risk factors for NDDs (OR > 1), whereas HEXIM2 (AD), TSC22D4 (AD), CHRNB1 (PD), BAG4 (PD), SLC25A1 (PD), and IL15 (PD) were protective factors (OR < 1). Molecular docking results revealed strong binding activities for PREDNISOLONE(ALPP = -7.6 kcal/mol), PANCURONIUM BROMIDE(CHRNB1 = -8 kcal/mol), CHEMBL379975(STK3 =-10.7 kcal/mol) and SIROLIMUS(IL15 = -9 kcal/mol). Molecular dynamics simulations confirmed the stable binding of the IL15-Sirolimus, ALPP-Prednisolone, STK3-CHEMBL379975, and CHRNB1-Rocuronium bromide complexes. This multi-omics study revealed 14 promising therapeutic targets for NDDs, providing new insights for targeted therapies and clinical strategies for NDDs. Our results provide evidence for future studies aimed at developing appropriate therapeutic interventions.
Molecular docking indicates that PREDNISOLONE (ALPP), PANCURONIUM BROMIDE (CHRNB1), CHEMBL379975 (STK3), and SIROLIMUS (IL15) are the most viable drug candidates for the treatment of both NDDs (Supplementary Table S13). Molecular dynamics simulations confirmed the stable binding of the IL15–Sirolimus, ALPP–Prednisolone, STK3–CHEMBL379975, and CHRNB1–Rocuronium bromide complexes.
Studies in PD patients have shown that Parkin and NIX support the formation of memory T cells by being upregulated in response to interleukin 15 (IL-15). IL-15, a cytokine involved in the survival and differentiation of T cells, stimulates the expression of Parkin and NIX, which are essential for maintaining mitochondrial integrity and regulating cellular energy. The upregulation of these proteins facilitates the metabolic and functional adaptations required for the generation and persistence of memory T cells, which are crucial for the adaptive immune response. Significant alterations in IL-15 have been observed in both the substantia nigra and striatum of patients with clinical PD32-35. The MR analysis indicates a protective role of IL15 in PD progression, consistent with foundational research outcomes. The IL-15-targeting drug LEVODOPA has been clinically approved for PD treatment. Molecular docking results suggest that SIROLIMUS may exhibit stronger ligand-protein binding compared to LEVODOPA (Supplementary Table S11, S13). The inhibition of mTOR activity by SIROLIMUS leads to autophagy activation. In a model of synucleinopathy, SIROLIMUS decreased α-synuclein accumulation, indicating that sirolimus treatment could prevent α-synuclein-induced neurodegeneration36. Through the Hippo pathway’s Mst1/2 (STK3/STK4), STK3 modulates autophagy under mitochondrial stress, maintaining mitochondrial stability and cellular integrity. In PD models, reduced Mst1 (STK3) expression helps mitigate the loss of TH-positive neurons, improving behavioral deficits and mitochondrial function37, further supporting its identification as a PD risk factor. CHEMBL379975 demonstrates the most optimal binding mode for targeting STK3 (Supplementary Table S11,S13). ALPP functions as a positive regulator of placental growth and is involved in essential cellular processes, including protein phosphorylation, cell growth, apoptosis, and migration during embryonic development. While no studies have yet established a direct association between ALPP and AD, it has been linked to increased disease risk. PREDNISOLONE treatment improves amyloid-beta (Aβ)-induced cognitive deficits in AD mice and inhibits microglial activation in the cortex and hippocampus. RNA sequencing analysis revealed that PREDNISOLONE ultimately salvages cognitive dysfunction by improving synaptic function and inhibiting immune and inflammatory processes38. PREDNISOLONE, which exhibits the strongest molecular affinity for ALPP, demonstrates significant therapeutic potential but requires further validation through fundamental research. CHRNB1 encodes the β subunit of the acetylcholine receptor at the neuromuscular junction, with mutations in this gene linked to congenital myasthenic syndrome (CMS)39,40. A potential relationship exists between CHRNB1 and tremor symptoms in PD, and our findings indicate a negative correlation with PD risk. Despite strong colocalization evidence, the precise mechanisms through which CHRNB1 mitigates PD risk remain to be determined. Among potential drugs, PANCURONIUM BROMIDE shows the highest promise for targeting CHRNB1 (Supplementary Table S11,S13).
Citrate also gets a mention @John_Hemming:
FXYD6 mRNA is essential for dendritic localization, and the loss of this localization is associated with impaired Na+/K±ATPase (NKA) function in dendrites, while NKA function in somatic cells remains unaffected. Additionally, FXYD6 expression is decreased in the brains of Tg2576 mice and human hippocampal tissues, suggesting that reduced FXYD6 expression may be detrimental to neurons. The dysfunction of Na+/K±ATPase due to low FXYD6 expression may lead to disrupted calcium balance, contributing to neurodegeneration by disturbing calcium homeostasis in NDDs48,49. LHFPL2 protein is abundantly expressed in malignant brain tissues and may play a role in linking cancer and PD genetically, potentially through interactions with TPM1. Short-term LPS treatment results in the downregulation of several genes associated with immune cell differentiation, including LHFPL2, suggesting a potential role for LHFPL2 in immune regulation and its involvement in the pathophysiology of NDDs like PD50. BAG4 functions as a negative regulator of Parkin translocation and works in concert with HSPA1L to regulate Parkin’s localization following mitochondrial damage in HeLa cells. Knockdown of HSPA1L significantly reduces Parkin translocation (P < 0.01), while knockdown of BAG4 enhances Parkin translocation, specifically in a PINK1-dependent manner, promoting Parkin’s relocation to damaged mitochondria51. Currently, research on the relationship between ENPP4 and PD is limited. ENPP4 and the PD-related gene PARK2 are located in the same chromosomal region, sparking interest in their potential association. However, existing studies have primarily focused on changes in gene expression and metabolic pathways, without investigating the specific role of ENPP4 in the pathogenesis of PD52. SLC25A1, a mitochondrial membrane transporter, is crucial for mitochondrial function regulation. Its expression is influenced by SUCLG1, which enhances mitochondrial mass and may increase SLC25A1 levels. Metabolite assays show a correlation between SLC25A1 expression and increased CA expression. In cells overexpressing SUCLG1, the addition of an SLC25A1 inhibitor partially restores PNF cell function, indicating that SUCLG1 affects PNF cell development through SLC25A1. In mice, abnormal SLC25A1 expression disrupts citrate/acetyl-CoA homeostasis, damages white matter integrity, and alters synaptic plasticity and morphology, potentially contributing to ASD-like phenotypes and proteomic changes. Our study identified IQCE, HDHD2, COMMD10, and FXYD6 as risk factors for AD, while HEXIM1 and TSC22D4 were associated with a reduced risk of AD. BAG4 and SLC25A1 were identified as protective factors for PD, while ENPP4 and LHFPL2 were linked to increased PD risk. However, the mechanisms through which these QTLs influence the two NDDs remain unclear and require further investigation.
Among these, PREDNISOLONE was identified as the most promising targeted drug for treating AD via ALPP, while PANCURONIUM BROMIDE, CHEMBL379975, and SIROLIMUS showed the highest potential for treating PD via CHRNB1, STK3, and IL15, respectively.
