Deep learning-driven decoding of ubiquitination: from regulatory mechanisms to targeted protein degradation.

Neurodegenerative diseases (NDDs) constitute a diverse group of neurological disorders that impact millions of individuals worldwide and are characterized by progressive degeneration or loss of neurons within the central and peripheral nervous system (Wilson et al., 2023). NDDs, which are associated with considerable morbidity and cognitive impairment, have an estimated prevalence of 9.33% worldwide (Wimo et al., 2017). Alzheimer’s disease (AD) (Long and Holtzman, 2019; Knopman et al., 2021), Parkinson’s disease (PD) (Poewe et al., 2017; Przedborski, 2017), Huntington’s disease (HD) (Bates et al., 2015; Jimenez-Sanchez et al., 2017), and amyotrophic lateral sclerosis (ALS) (Kiernan et al., 2011; Rohrer et al., 2015) are the most common NDDs. Neural network collapse and the loss of neurons, which cannot be regenerated owing to their terminally differentiated state, disrupt core communication pathways, leading to deficits in memory, cognition, behavior, sensory processing, and/or motor function (Erkkinen et al., 2018). Thus, identifying the etiology and underlying molecular mechanisms of cognitive impairment in NDDs is important for developing effective therapies to improve patients’ quality of life. High levels of homocysteine (Hcy), a physiological amino acid generated during protein metabolism, cause a pathological condition known as hyperhomocysteinemia (hHcy), which was first reported as a factor contributing to cardiovascular disease (Ganguly and Alam, 2015; Gospodarczyk et al., 2022). Recent evidence has demonstrated that hHcy is epidemiologically and clinically associated with various pathological conditions and is a risk factor for NDDs (Schalinske and Smazal, 2012; Cordaro et al., 2021). Methionine (Met) is an essential amino acid that is involved in Hcy production via the methionine cycle and is a key methyl donor in cellular metabolism (Froese et al., 2019). Chronic consumption of a high-methionine diet (HMD) induces a state of hHcy, which may promote amyloid-β (Aβ) overproduction, Tau protein hyperphosphorylation, neuronal loss, inflammation, and oxidative stress, leading to cognitive impairment (Grinan-Ferre et al., 2018; Qureshi et al., 2019; Wang et al., 2022). Hcy is generally thought to induce cell damage via oxidative stress (Kolling et al., 2011; Scherer et al., 2011). Specifically, Hcy-induced oxidative stress has been linked to energy metabolism changes in NDDs (Zhou et al., 2023). Hcy is a physiological metabolite of the methionine cycle, which generates S-adenosylmethionine, the most important methyl donor for DNA methylation and epigenetic regulation (Froese et al., 2019). However, it is unclear whether Hcy regulates histone modification in the context of cognitive impairment. Posttranslational modifications (PTMs) of protein lysine residues (e.g., acetylation, succinylation, lactylation, and malonylation) play important roles in regulating cellular functions in both physiological and pathological states (Wang and Lin, 2021; Fu et al., 2022). Acetylation is a PTM that is involved in the regulation of both histone and non-histone proteins. Acetylation is crucial for maintaining neuronal plasticity and plays an essential role in memory formation and learning (Kabir et al., 2022). Acetylation homeostasis is regulated by the coordinated activities of histone acetyltransferases (HATs) and histone deacetylases (HDACs). Dysregulation of these tightly controlled processes has been implicated in several NDDs, including AD, PD, HD, and ALS (Khan et al., 2021; Kabir et al., 2022; Lin et al., 2023). Chai et al. (2024) reported that, in hHcy rats, levels of the permissive histone marker trimethyl histone H3 lysine 4 and its methyltransferase lysine methyltransferase 2B were significantly increased, impairing synaptic plasticity and cognitive function, which highlights the role of histone acetylation in Hcy-related cognitive disorders. In addition, histone H3 lysine 27 acetylation (H3K27ac) and H3K9ac disrupt feedback loops that regulate the expression of transcription- and chromatin-related genes in AD, suggesting potential epigenetic strategies for early-stage AD treatment (Nativio et al., 2020). In HD models, transcriptional and histone acetylation–related alterations highlight key cis-regulatory elements factors affecting disease pathology in the early stages (Arancibia-Opazo et al., 2023). These studies suggest important roles for histone acetylation and its associated enzymes in NDDs. However, the specific mechanism by which histone acetylation modifies Hcy-induced cognitive impairment remains unclear.