bims-mistre 2025-08-03 papers

bims-mistre

Biomed News

on Mito stress

Issue of 2025–08–03
twelve papers selected by
Ellen Siobhan Mitchell, MitoQ

Aberrant S-nitrosylation in the TCA cycle contributes to mitochondrial dysfunction, energy compromise, and synapse loss in neurodegenerative diseases.
Oxidative Stress: Oocyte Quality and Infertility.
Mitochondrial Damage and Autophagy Dysregulation in Alzheimer's Disease: Mechanisms and Therapeutic Opportunities.
Metabolic Disturbances Involved in Cardiovascular Diseases: The Role of Mitochondrial Dysfunction, Altered Bioenergetics and Oxidative Stress.
Oral Prodrug of a Novel Glutathione Surrogate Reverses Metabolic Dysregulation and Attenuates Neurodegenerative Process in Transgenic Alzheimer's Mice.
Role of impaired mitochondrial dynamics and mitophagy in cardiovascular diseases: Possible therapeutic approaches.
The Therapeutic Potential of Butyrate and Lauric Acid in Modulating Glial and Neuronal Activity in Alzheimer's Disease.
Postbiotics as Mitochondrial Modulators in Inflammatory Bowel Disease: Mechanistic Insights and Therapeutic Potential.
Aerobic exercise rescues synaptic plasticity in early-stage Alzheimer's disease by suppressing miR-3473e to activate EphB2-dependent NMDA/AMPA receptor signaling.
12,13-diHOME protects against the age-related decline in cardiovascular function via attenuation of CaMKII.
Proteasomal dysfunction in the mouse forebrain induces mitochondrial DNA release, cGAS-STING signaling activation, and necroptosis.
Elevated ubiquitin phosphorylation by PINK1 contributes to proteasomal impairment and promotes neurodegeneration.

Neurotherapeutics. 2025 Jul 28. pii: S1878-7479(25)00186-2. [Epub ahead of print] e00708

Aberrant S-nitrosylation in the TCA cycle contributes to mitochondrial dysfunction, energy compromise, and synapse loss in neurodegenerative diseases.

Tomohiro Nakamura, Anamika Sharma, Stuart A Lipton.

  Neuronal synaptic activity relies heavily on mitochondrial energy production, as synaptic transmission requires substantial ATP. Accordingly, mitochondrial dysfunction represents a key underlying factor in synaptic loss that strongly correlates with cognitive decline in Alzheimer's disease and other neurocognitive disorders. Increasing evidence suggests that elevated nitro-oxidative stress impairs mitochondrial bioenergetic function, leading to synaptic degeneration. In this review, we highlight the pathophysiological roles of nitric oxide (NO)-dependent posttranslational modifications (PTMs), particularly S-nitrosylation of cysteine residues, and their impact on mitochondrial metabolism. We focus on the pathological S-nitrosylation of tricarboxylic acid cycle enzymes, particularly α-ketoglutarate dehydrogenase, as well as electron transport chain proteins. This aberrant PTM disrupts mitochondrial energy production. Additionally, we discuss the consequences of aberrant protein S-nitrosylation on mitochondrial dynamics and mitophagy, further contributing to mitochondrial dysfunction and synapse loss. Finally, we examine current strategies to ameliorate S-nitrosylation-mediated mitochondrial dysfunction in preclinical models of neurodegenerative diseases and explore future directions for developing neurotherapeutics aimed at restoring mitochondrial metabolism in the context of nitro-oxidative stress.

Keywords:  Cognitive decline; Protein S-nitrosylation; Synapse loss; TCA cycle; α-Ketoglutarate dehydrogenase

DOI:  https://doi.org/10.1016/j.neurot.2025.e00708
Reprod Toxicol. 2025 Jul 23. pii: S0890-6238(25)00182-0. [Epub ahead of print] 109011

Oxidative Stress: Oocyte Quality and Infertility.

Ismat Ara Begum.

  Infertility affects a significant proportion of couples worldwide, with female reproductive dysfunction contributing to nearly half of these cases. Oxidative Stress (OS), characterized by an imbalance between Reactive Oxygen Species (ROS) production and antioxidant defenses, has emerged as a critical factor influencing oocyte quality and female fertility. This review examines the origins of OS both in vivo and in vitro, highlighting mitochondria and granulosa cells as primary sources, and explores the impact of ovarian aging, obesity, hyperoxic culture conditions, and environmental exposures such as cigarette smoke, endocrine-disrupting chemicals, and controlled ovarian stimulation drugs. This work further explores how OS adversely affects oocyte quality through mechanisms including mitochondrial dysfunction, follicular atresia, meiotic errors, DNA damage, telomere shortening, and reduced fertilization rates. Additionally, this review explores reproductive disorders associated with OS, including polycystic ovary syndrome, endometriosis, premature ovarian insufficiency, and miscarriage. The implications of OS in ART are also addressed, emphasizing the need for strategies to mitigate oxidative damage in both clinical and environmental contexts. This review underscores the significance of OS in female reproductive health, paving the way for potential therapeutic interventions to enhance fertility outcomes.

Keywords:  Assisted Reproductive Technologies; Endometriosis; Follicles; Oogenesis; Polycystic Ovary Syndrome; Reactive Oxygen Species; Spindle

DOI:  https://doi.org/10.1016/j.reprotox.2025.109011
Neurochem Res. 2025 Jul 28. 50(4): 251

Mitochondrial Damage and Autophagy Dysregulation in Alzheimer's Disease: Mechanisms and Therapeutic Opportunities.

Qian Yu, Li Li, Shuyi Yu, Jialin Han, Qian Cheng, Zhikang Cui, Hang Chen, Ming Li, Zhiming Lu.

  Alzheimer's disease (AD) is a neurodegenerative disorder that causes progressive neurodegeneration and a variety of cognitive deficits. Of note, mitochondrial malfunctions occur early in the disease's development. Mitophagy impairment leads to the build-up of damaged mitochondria inside the cells, causing malfunction and eventual death of the cells. This review summarizes the mechanisms linking mitochondrial damage and autophagy dysregulation to AD and highlights potential therapeutic opportunities. We summarize how mitochondrial dysfunction contributes to AD, including defects in mitochondrial biogenesis, impaired dynamics, the impact of AD-related protein aggregates on mitochondrial integrity, and defective axonal transport. We also explore the roles of mitophagy in AD, including its function in the removal of harmed proteins and organelles. Finally, we highlight the therapeutic strategies for the treatment of AD, targeting molecular components involved in mitochondrial damage and autophagy dysregulation in AD, i.e., antioxidants, mitochondrial modulators, and mitophagy enhancers.

Keywords:  Alzheimer’s disease; Aβ; Mitochondrial dysfunction; Mitophagy; p-tau

DOI:  https://doi.org/10.1007/s11064-025-04490-z
Int J Mol Sci. 2025 Jul 15. pii: 6791. [Epub ahead of print]26(14):

Metabolic Disturbances Involved in Cardiovascular Diseases: The Role of Mitochondrial Dysfunction, Altered Bioenergetics and Oxidative Stress.

Donatella Pietrangelo, Caroline Lopa, Margherita Litterio, Maria Cotugno, Speranza Rubattu, Angela Lombardi.

  The study of metabolic abnormalities regarding mitochondrial respiration and energy production has significantly advanced our understanding of cell biology and molecular mechanisms underlying cardiovascular diseases (CVDs). Mitochondria provide 90% of the energy required for maintaining normal cardiac function and are central to heart bioenergetics. During the initial phase of heart failure, mitochondrial number and function progressively decline, causing a decrease in oxidative metabolism and increased glucose uptake and glycolysis, leading to ATP depletion and bioenergetic starvation, finally contributing to overt heart failure. Compromised mitochondrial bioenergetics is associated with vascular damage in hypertension, vascular remodeling in pulmonary hypertension and acute cardiovascular events. Thus, mitochondrial dysfunction, leading to impaired ATP production, excessive ROS generation, the opening of mitochondrial permeability transition pores and the activation of apoptotic and necrotic pathways, is revealed as a typical feature of common CVDs. Molecules able to positively modulate cellular metabolism by improving mitochondrial bioenergetics and energy metabolism and inhibiting oxidative stress production are expected to exert beneficial protective effects in the heart and vasculature. This review discusses recent advances in cardiovascular research through the study of cellular bioenergetics in both chronic and acute CVDs. Emerging therapeutic strategies, specifically targeting metabolic modulators, mitochondrial function and quality control, are discussed.

Keywords:  cardiac bioenergetics; cardiovascular diseases; glycolysis; metabolic flux analyzers; metabolic reprogramming; mitochondria

DOI:  https://doi.org/10.3390/ijms26146791
ACS Pharmacol Transl Sci. 2025 Jul 18.

Oral Prodrug of a Novel Glutathione Surrogate Reverses Metabolic Dysregulation and Attenuates Neurodegenerative Process in Transgenic Alzheimer's Mice.

Swetha Pavani Rao, Aminat O Imam-Fulani, Wei Xie, Samuel Phillip, Krishna Chennavajula, Kiran D Bhilare, Erin B Lind, Ying Zhang, Robert Vince, Michael K Lee, Swati S More.

  Glycation-induced oxidative stress underlies the numerous metabolic ravages of Alzheimer's disease (AD). Reduced glutathione levels in AD lead to increased oxidative stress, including glycation-induced pathology. Previously, we showed that the accumulation of reactive 1,2-dicarbonyls such as methylglyoxal, the major precursor of nonenzymatic glycation products, was reduced by the increased function of GSH-dependent glyoxalase-1 enzyme in the brain. In this two-pronged study, we evaluate the therapeutic efficacy of an orally bioavailable prodrug of our lead glyoxalase substrate, pro-ψ-GSH, for the first time in a transgenic Alzheimer's disease mouse model. This prodrug delivers pharmacodynamically relevant brain concentrations of ψ-GSH upon oral delivery. Chronic oral dosing of pro-ψ-GSH effectively reversed the cognitive decline observed in the APP/PS1 mouse model. The prodrug successfully mirrors the robust effects of the parent drug, i.e., reducing amyloid pathology, glycation stress, neuroinflammation, and the resultant neurodegeneration, in these mice. We also report the first metabolomics study of such a treatment that yields key biomarkers linked to the reversal of AD-related metabolic dysregulation. Collectively, this study demonstrates the neuroprotective effect of pro-ψ-GSH in a symptomatic preclinical model of AD and paves the way for further preclinical advancement of such therapeutics. Metabolomic signatures identified could prove beneficial in the development of treatment-specific, clinically translatable biomarkers.

Keywords:  Alzheimer’s disease; advanced glycation end products; glyoxalase-1; metabolomics; neuroinflammation; oxidative stress

DOI:  https://doi.org/10.1021/acsptsci.5c00031
Life Sci. 2025 Jul 30. pii: S0024-3205(25)00525-9. [Epub ahead of print] 123890

Role of impaired mitochondrial dynamics and mitophagy in cardiovascular diseases: Possible therapeutic approaches.

Sarmistha Sarkar, Aindrila Chattopadhyay, Debasish Bandyopadhyay.

  High mortality rates due to cardiovascular diseases (CVDs) fascinate the scientists worldwide in the past few decades to discover potent therapeutic strategies to save the victims. The myocardium being a highly active tissue, mitochondrial homeostasis and mitochondrial quality control system are crucial for maintaining optimal cardiac performance. Mitochondrial quality control mechanism is a finely tuned regulatory network encompassing mitochondrial biogenesis, mitochondrial dynamics and mitophagy and is an integral component of the mitochondrial response to stressor stimuli. Mitochondrial dynamics including the fusion and fission of mitochondrial membranes is regulated by an extensively conserved mechanism comprising a group of mitochondrial membrane proteins belonging to the dynamin family of GTPases. Emerging evidences indicate that defects in mitochondrial fusion or fission are intrinsically correlated with the pathophysiology of CVDs. Mitophagy is a kind of selective autophagy which removes damaged or redundant mitochondria. Experimental findings demonstrated that impairment of mitophagy in cardiomyocytes induces the accumulation of dysfunctional mitochondria, leading to the disruption of cellular homeostasis and consequently precipitating various CVDs. These findings speculate that pharmacological modulation of mitochondrial homeostasis including mitochondrial dynamics and mitophagy may represent a potential therapeutic approach in restoring cardiac physiology. This review summarizes the prevailing insight into the impact of disturbed mitochondrial dynamics and mitophagy in the pathogenesis of CVDs and also delineates the therapeutic potential of several relevant regulatory drugs that target mitochondrial function and quality control in alleviating mitochondrial impairment-related cardiac dysfunction.

Keywords:  Cardiomyocytes; Cardiovascular diseases; Mitochondrial dynamics; Mitochondrial dysfunction; Mitophagy

DOI:  https://doi.org/10.1016/j.lfs.2025.123890
Nutrients. 2025 Jul 10. pii: 2286. [Epub ahead of print]17(14):

The Therapeutic Potential of Butyrate and Lauric Acid in Modulating Glial and Neuronal Activity in Alzheimer's Disease.

Rathnayaka Mudiyanselage Uththara Sachinthanie Senarath, Lotta E Oikari, Prashant Bharadwaj, Vijay Jayasena, Ralph N Martins, Wanakulasuriya Mary Ann Dipika Binosha Fernando.

  Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by amyloid-β plaque accumulation, tau tangles, and extensive neuroinflammation. Neuroinflammation, driven by glial cells like microglia and astrocytes, plays a critical role in AD progression. Initially, these cells provide protective functions, such as debris clearance and neurotrophic support. However, as AD progresses, chronic activation of these cells exacerbates inflammation, contributing to synaptic dysfunction, neuronal loss, and cognitive decline. Microglia release pro-inflammatory cytokines and reactive oxygen species (ROS), while astrocytes undergo reactive astrogliosis, further impairing neuronal health. This maladaptive response from glial cells significantly accelerates disease pathology. Current AD treatments primarily aim at symptomatic relief, with limited success in disease modification. While amyloid-targeting therapies like Aducanumab and Lecanemab show some promise, their efficacy remains limited. In this context, natural compounds have gained attention for their potential to modulate neuroinflammation and promote neuroprotection. Among these, butyrate and lauric acid are particularly notable. Butyrate, produced by a healthy gut microbiome, acts as a histone deacetylase (HDAC) inhibitor, reducing pro-inflammatory cytokines and supporting neuronal health. Lauric acid, on the other hand, enhances mitochondrial function, reduces oxidative stress, and modulates inflammatory pathways, thereby supporting glial and neuronal health. Both compounds have been shown to decrease amyloid-β deposition, reduce neuroinflammation, and promote neuroprotection in AD models. This review explores the mechanisms through which butyrate and lauric acid modulate glial and neuronal activity, highlighting their potential as therapeutic agents for mitigating neuroinflammation and slowing AD progression.

Keywords:  Alzheimer’s disease; astrocytes; butyrate; lauric acid; microglia; neurons

DOI:  https://doi.org/10.3390/nu17142286
Biomolecules. 2025 Jul 01. pii: 954. [Epub ahead of print]15(7):

Postbiotics as Mitochondrial Modulators in Inflammatory Bowel Disease: Mechanistic Insights and Therapeutic Potential.

Santosh Kumar Prajapati, Dhananjay Yadav, Shweta Katiyar, Shalini Jain, Hariom Yadav.

  Postbiotics, which are non-viable microbial derivatives including short-chain fatty acids (SCFAs), microbial peptides, and cell wall components, are emerging as novel therapeutic agents for Inflammatory Bowel Disease (IBD). Unlike probiotics, postbiotics offer a safer, more stable alternative while retaining potent bioactivity. IBD, encompassing Crohn's disease and ulcerative colitis, is characterized by chronic gastrointestinal inflammation, epithelial barrier dysfunction, and immune dysregulation. Recent evidence links mitochondrial dysfunction marked by impaired energy metabolism, oxidative stress, and apoptosis with the pathogenesis and persistence of IBD. Postbiotics have shown the ability to modulate mitochondrial health through multiple mechanisms. SCFAs such as butyrate serve as primary energy substrates for colonocytes, enhancing mitochondrial respiration and promoting biogenesis. They improve mitochondrial function and boost ATP production. Moreover, postbiotics reduce oxidative damage by regulating antioxidant defenses. These antioxidant actions limit epithelial apoptosis and preserve cellular integrity. In addition, postbiotics regulate mitophagy and help maintain mitochondrial quality and reduce inflammation. Structural components such as lipoteichoic acid and peptidoglycan have been shown to interact with mitochondrial pathways and modulate inflammatory responses. Collectively, this review explores the interplay between mitochondrial dysfunction, IBD, and preventive approach using postbiotics. Understanding the connections with postbiotics could open up new avenues for therapeutic interventions aimed at mitigating IBD severity in people with IBD.

Keywords:  IBD; ROS; mitochondrial dysfunction; oxidative stress; postbiotics

DOI:  https://doi.org/10.3390/biom15070954
Neurochem Int. 2025 Jul 26. pii: S0197-0186(25)00096-8. [Epub ahead of print] 106023

Aerobic exercise rescues synaptic plasticity in early-stage Alzheimer's disease by suppressing miR-3473e to activate EphB2-dependent NMDA/AMPA receptor signaling.

Xiangli Tong, Zhen Tong, Weijia Wu, Jialun Yang, Juan Wang, Yang Wang, Dandan Chen, Yiyang Wang, Fanqi Zeng, Qiyan Du, Yishan Chen, Wenfeng Liu.

  Cognitive dysfunction in early-stage Alzheimer's disease (AD) involves significant impairments in synaptic plasticity and dendritic spines integrity. Intriguingly, exercise interventions have demonstrated efficacy in enhancing cognitive function. However, the precise molecular mechanisms, particularly the upstream endogenous regulators (such as miRNAs) through which exercise mediates this synaptic improvement, remain unclear. Our findings indicated that 12 weeks of aerobic exercise effectively increased learning and memory, promoted amyloid beta (Aβ) and cerebral amyloid angiopathy (CAA) clearance in early-stage AD. Furthermore, aerobic exercise markedly enhanced dendritic spines density of pyramidal neurons in cortical layers II/III and the hippocampal CA1 region, as well as the expression of synapse-associated proteins such as cAMP response element-binding protein (CREB), synaptophysin (SYN), and postsynaptic density protein 95 (PSD95). Whole genome RNA sequencing (RNA-Seq) and bioinformatics analysis was performed to identify miR-3473e, a target closely related to AD and also a response factor that serves as a key mediator of aerobic exercise benefits. Subsequent findings revealed that miR-3473e was overexpressed in the brains of APP/PS1 mice, whereas aerobic exercise led to a decrease in its expression. Moreover, aerobic exercise enhanced its downstream targets, EPH receptor B2 (EphB2) and solute carrier family 1 member 1 gene (Slc1a1) as well as increased downstream GluN1, GRIA1 and p-GluN2B/GluN2B protein expression levels. In summary, we demonstrate that aerobic exercise can improve synaptic plasticity, and these effects are mediated via suppression of miR-3473e and regulation EphB2-NMDA/AMPA receptor signaling pathway, underscoring the potential of aerobic exercise to enhance cognitive function in early-stage of AD.

Keywords:  APP/PS1; Aerobic exercise; EPH Receptor B2; Synaptic plasticity; miR-3473e

DOI:  https://doi.org/10.1016/j.neuint.2025.106023
Nat Commun. 2025 Aug 02. 16(1): 7088

12,13-diHOME protects against the age-related decline in cardiovascular function via attenuation of CaMKII.

Shinsuke Nirengi, Benjamin Buck, Devleena Das, Carmem Peres Valgas da Silva, Jazmin Calyeca, Lisa A Baer, Hsiang-Ling Huang, Pablo Vidal, Revati S Dewal, Kelsey M Pinckard, Elisa Félix-Soriano, Diego Hernandez-Saavedra, Andrew Gerea, Kavya Dathathreya, Silvia Duarte-Sanmiguel, Ty A Saldana, Harrison L Hookfin, Matthew W Gorr, Valerie Bussberg, Juan J Aristizabal-Henao, Michael A Kiebish, Roeland J W Middelbeek, Laurie J Goodyear, Paul M Coen, Krishna Chinthalapudi, Loren E Wold, Ana L Mora, Thomas J Hund, Daniel Gallego-Perez, Kristin I Stanford.

Aging poses significant challenges to cardiovascular health necessitating novel therapeutic approaches. This study investigates the potential of the brown adipose tissue (BAT) derived lipokine 12,13-diHOME to mitigate age-induced impairments in cardiovascular function. Analysis of human and rodent plasma signaling lipids reveals a decline in 12,13-diHOME levels with age. Transplantation of BAT or sustained upregulation of 12,13-diHOME effectively preserved cardiac function in aged male and female mice. Bulk RNA-Seq of hearts from aged mice reveals significant increases in pathways involved in ER stress and fibrosis which were partially attenuated by BAT transplantation or sustained upregulation of 12,13-diHOME. Mechanistically, in vivo and in vitro models demonstrate that 12,13-diHOME alleviated ER stress through CaMKII inhibition, particularly in males. These findings underscore 12,13-diHOME as a promising candidate for combating age-related cardiovascular dysfunction, offering insights into potential therapeutic strategies for addressing cardiovascular diseases in aging populations.

DOI: https://doi.org/10.1038/s41467-025-62474-7
J Neuropathol Exp Neurol. 2025 Aug 01. pii: nlaf093. [Epub ahead of print]

Proteasomal dysfunction in the mouse forebrain induces mitochondrial DNA release, cGAS-STING signaling activation, and necroptosis.

Abena Dwamena, Yasin Asadi, Erin Gilstrap, Hongmin Wang.

  Impaired proteasome function is associated with various neurodegenerative disorders that are hallmarked by neuroinflammation and neurodegeneration, including Alzheimer disease (AD); however, the relationships between these phenomena remain unclear. By utilizing a neuron-specific Psmc1 conditional knockout (cKO) mouse model in which one of the 19S proteasome is disrupted, we studied the effect of impaired proteasome function on neuroinflammation and neuronal death in the brain. We discovered that disrupting the 19S proteasome led to increased release of mitochondrial double-stranded DNA into the cytosol, upregulated levels of cyclic GMP-AMP synthase (cGAS), stimulator of interferon gene (STING), phosphorylated TBK1, and IRF3, and the downstream pro-inflammatory mediators, including STAT1, NF-κB, IL-1β, IL-6, and TNFα in the cKO mouse brains as compared to control brains. Importantly, we also observed reduced brain weight and elevation in levels of factors involved in necroptosis, ie the mixed lineage kinase domain-like (MLKL) protein, phosphorylated MLKL, and receptor-interacting protein kinases (RIPK) 1 and 3 in the cKO mouse brains. Together, our data suggest that proteasome dysfunction activates the cGAS-STING pathway and induces neuroinflammation and necroptotic neuronal death.

Keywords:  cGAS-STING; necroptosis; neurodegenerative disease; neuroinflammation; proteasome; proteasome dysfunction

DOI:  https://doi.org/10.1093/jnen/nlaf093
Elife. 2025 Jul 31. pii: RP103945. [Epub ahead of print]14

Elevated ubiquitin phosphorylation by PINK1 contributes to proteasomal impairment and promotes neurodegeneration.

Cong Chen, Tong-Yao Gao, Hua-Wei Yi, Yi Zhang, Tong Wang, Zhi-Ling Lou, Tao-Feng Wei, Yun-Bi Lu, Tingting Li, Chun Tang, Wei-Ping Zhang.

  Ubiquitin (Ub), a central regulator of protein turnover, can be phosphorylated by PINK1 (PTEN-induced putative kinase 1) to generate S65-phosphorylated ubiquitin (pUb). Elevated pUb levels have been observed in aged human brains and in Parkinson's disease, but the mechanistic link between pUb elevation and neurodegeneration remains unclear. Here, we demonstrate that pUb elevation is a common feature under neurodegenerative conditions, including Alzheimer's disease, aging, and ischemic injury. We show that impaired proteasomal activity leads to the accumulation of sPINK1, the cytosolic form of PINK1 that is normally proteasome-degraded rapidly. This accumulation increases ubiquitin phosphorylation, which then inhibits ubiquitin-dependent proteasomal activity by interfering with both ubiquitin chain elongation and proteasome-substrate interactions. Specific expression of sPINK1 in mouse hippocampal neurons induced progressive pUb accumulation, accompanied by protein aggregation, proteostasis disruption, neuronal injury, neuroinflammation, and cognitive decline. Conversely, Pink1 knockout mitigated protein aggregation in both mouse brains and HEK293 cells. Furthermore, the detrimental effects of sPINK1 could be counteracted by co-expressing Ub/S65A phospho-null mutant but exacerbated by over-expressing Ub/S65E phospho-mimic mutant. Together, these findings reveal that pUb elevation, triggered by reduced proteasomal activity, inhibits proteasomal activity and forms a feedforward loop that drives progressive neurodegeneration.

Keywords:  PINK1; biochemistry; chemical biology; mouse; neurodegeneration; phosphorylation; proteasome; ubiquitin

DOI:  https://doi.org/10.7554/eLife.103945