sumo neuron

OBJECTIVES: Astragaloside IV (AST IV) and ligustrazine (Lig), the main ingredients of Astragali Radix and Chuanxiong Rhizoma respectively, have demonstrated significant benefits in treatment of cerebral ischemia -reperfusion injury (CIRI); however, the mechanisms underlying its benificial effects remain unclear. SUMO-1ylation and deSUMO-2/3ylation of dynamin-related protein 1 (Drp1) results in mitochondrial homeostasis imbalance following CIRI, which subsequently aggravates cell damage...

Rhes (Ras homolog enriched in the striatum), a multifunctional protein that regulates striatal functions associated with motor behaviors and neurological diseases, can shuttle from cell to cell via the formation of tunneling-like nanotubes (TNTs). However, the mechanisms by which Rhes mediates diverse functions remain unclear. Rhes is a small GTPase family member which contains a unique C-terminal Small Ubiquitin-like Modifier (SUMO) E3-like domain that promotes SUMO post-translational modification of proteins (SUMOylation) by promoting "cross-SUMOylation" of the SUMO enzyme SUMO E1 (Aos1/Uba2) and SUMO E2 ligase (Ubc-9)...

Activated small ubiquitin-like modifiers (SUMOs) have been implicated in neuropathological processes following ischemic stroke. However, the target proteins of SUMOylation and their contribution to neuronal injury remain to be elucidated. MLK3 (mixed-lineage kinase 3), a member of the mitogen-activated protein kinase kinase kinase (MAPKKK) family, is a critical regulator of neuronal lesions following cerebral ischemia. Here, we found that SUMOylation of MLK3 increases in both global and focal ischemic rodent models and primary neuronal models of oxygen and glucose deprivation (OGD)...

Recent studies have shown that nucleophagy can mitigate DNA damage by selectively degrading nuclear components protruding from the nucleus. However, little is known about the role of nucleophagy in neurons after spinal cord injury (SCI). Western blot analysis and immunofluorescence were performed to evaluate the nucleophagy after nuclear DNA damage and leakage in SCI neurons in vivo and NSC34 expression in primary neurons cultured with oxygen-glucose deprivation (OGD) in vitro, as well as the interaction and colocalization of autophagy protein LC3 with nuclear lamina protein Lamin B1...

Tau is a microtubule-associated protein essential for microtubule assembly and stability in neurons. The abnormal intracellular accumulation of tau aggregates is a major characteristic of brains from patients with Alzheimer's disease (AD) and other tauopathies. In AD, the presence of neurofibrillary tangles (NFTs), which is composed of hyperphosphorylated tau protein, is positively correlated with the severity of the cognitive decline. Evidence suggests that the accumulation and aggregation of tau cause synaptic dysfunction and neuronal degeneration...

Alzheimer's disease is the most prevalent neurodegenerative disease affecting older adults. Primary features of Alzheimer's disease include extracellular aggregation of amyloid-β plaques and the accumulation of neurofibrillary tangles, formed by tau protein, in the cells. While there are amyloid-β-targeting therapies for the treatment of Alzheimer's disease, these therapies are costly and exhibit potential negative side effects. Mounting evidence suggests significant involvement of tau protein in Alzheimer's disease-related neurodegeneration...

Emerging evidence highlights the relevance of the protein post-translational modification by SUMO (Small Ubiquitin-like Modifier) in the central nervous system for modulating cognition and plasticity in health and disease. In these processes, astrocyte-to-neuron crosstalk mediated by extracellular vesicles (EVs) plays a yet poorly understood role. Small EVs (sEVs), including microvesicles and exosomes, contain a molecular cargo of lipids, proteins, and nucleic acids that define their biological effect on target cells...

Diabetic peripheral neuropathy (DPN) is the prevalent type of peripheral neuropathy; it primarily impacts extremity nerves. Its multifaceted nature makes the molecular mechanisms of diabetic neuropathy intricate and incompletely elucidated. Several types of post-translational modifications (PTMs) have been implicated in the development and progression of DPN, including phosphorylation, glycation, acetylation and SUMOylation. SUMOylation involves the covalent attachment of small ubiquitin-like modifier (SUMO) proteins to target proteins, and it plays a role in various cellular processes, including protein localization, stability, and function...

The voltage-gated sodium channel NaV1.7 is an essential component of human pain signaling. Changes in NaV1.7 trafficking are considered critical in the development of neuropathic pain. SUMOylation of collapsin response mediator protein 2 (CRMP2) regulates the membrane trafficking and function of NaV1.7. Enhanced CRMP2 SUMOylation in neuropathic pain correlates with increased NaV1.7 activity. Pharmacological and genetic interventions that interfere with CRMP2 SUMOylation in rodents with neuropathic pain have been shown to reverse mechanical allodynia...

Dysregulation of voltage-gated sodium NaV1.7 channels in sensory neurons contributes to chronic pain conditions, including trigeminal neuropathic pain. We previously reported that chronic pain results in part from increased SUMOylation of collapsin response mediator protein 2 (CRMP2), leading to an increased CRMP2/NaV1.7 interaction and increased functional activity of NaV1.7. Targeting this feed-forward regulation, we developed compound 194, which inhibits CRMP2 SUMOylation mediated by the SUMO-conjugating enzyme Ubc9...

SUMO (small ubiquitin-like modifier) conjugation or SUMOylation, a post-translational modification, is a crucial regulator of protein function and cellular processes. In the context of neural stem cells (NSCs), SUMOylation has emerged as a key player, affecting their proliferation, differentiation, and survival. By modifying transcription factors, such as SOX1, SOX2, SOX3, SOX6, Bmi1, and Nanog, SUMOylation can either enhance or impair their transcriptional activity, thus impacting on NSCs self-renewal. Moreover, SUMOylation regulates neurogenesis and neuronal differentiation by modulating key proteins, such as Foxp1, Mecp2, MEF2A, and SOX10...

Nucleocytoplasmic transport comprises the multistep assembly, transport and disassembly of protein and RNA cargoes entering and exiting nuclear pores. Accruing evidence supports that impairments to nucleocytoplasmic transport are a hallmark of neurodegenerative diseases. These impairments cause dysregulations in nucleocytoplasmic partitioning and proteostasis of nuclear transport receptors and client substrates that promote intracellular deposits - another hallmark of neurodegeneration. Disturbances in liquid-liquid phase separation (LLPS) between dense and dilute phases of biomolecules implicated in nucleocytoplasmic transport promote micrometer-scale coacervates, leading to proteinaceous aggregates...

Advances in genome sequencing technologies have favored the identification of rare de novo mutations linked to neurological disorders in humans. Recently, a de novo autosomal dominant mutation in NACC1 was identified (NM_052876.3: c.892C > T, NP_443108.1; p.Arg298Trp), associated with severe neurological symptoms including intellectual disability, microcephaly, and epilepsy. As NACC1 had never before been associated with neurological diseases, we investigated how this mutation might lead to altered brain function...

Dysregulation of voltage-gated sodium Na V 1.7 channels in sensory neurons contributes to chronic pain conditions, including trigeminal neuropathic pain. We previously reported that chronic pain results in part from increased SUMOylation of collapsin response mediator protein 2 (CRMP2), leading to an increased CRMP2/Na V 1.7 interaction and increased functional activity of Na V 1.7. Targeting this feed-forward regulation, we developed compound 194 , which inhibits CRMP2 SUMOylation mediated by the SUMO-conjugating enzyme Ubc9...

Small molecules directly targeting the voltage-gated sodium channel (VGSC) NaV 1.7 have not been clinically successful. We reported that preventing the addition of a small ubiquitin-like modifier onto the NaV 1.7-interacting cytosolic collapsin response mediator protein 2 (CRMP2) blocked NaV 1.7 function and was antinociceptive in rodent models of neuropathic pain. Here, we discovered a CRMP2 regulatory sequence (CRS) unique to NaV 1.7 that is essential for this regulatory coupling. CRMP2 preferentially bound to the NaV 1...

The nucleoside guanosine is an endogenous neuromodulator associated with neuroprotection. The roles of guanosine during aging are still not fully elucidated. Guanosine modulates SUMOylation in neurons and astrocytes in vitro, but it is not known whether guanosine can modulate SUMOylation in vivo and improve cognitive functions during aging. SUMOylation is a post-translational protein modification with potential neuroprotective roles. In this follow-up study, we investigated whether guanosine could modulate SUMOylation in vivo and behavior in young and aged mice...

The small, ubiquitin-like modifier (SUMO) is a post-translational modifier with a profound influence on several key biological processes, including the mammalian stress response. Of particular interest are its neuroprotective effects, first recognized in the 13-lined ground squirrel ( Ictidomys tridecemlineatus ), in the context of hibernation torpor. Although the full scope of the SUMO pathway is yet to be elucidated, observations of its importance in managing neuronal responses to ischemia, maintaining ion gradients, and the preconditioning of neural stem cells make it a promising therapeutic target for acute cerebral ischemia...

Chronic intermittent hypoxia (CIH) is a characteristic pathophysiological change of obstructive sleep apnea syndrome (OSAS). Inflammation of microglia induced by CIH, plays a vital role in OSAS-associated cognitive dysfunction. SUMO-specific proteases 1 (SENP1) has been implicated in tumor inflammatory microenvironment and cells migration. However, the role of SENP1 in CIH-induced neuroinflammation remains unknown. We aimed to investigate the effect of SENP1 on neuroinflammation and neuronal injury. After the preparation of SENP1 overexpression microglia and SENP1 knockout mouse, CIH microglia and mice were established using an intermittent hypoxia device...

Glucocorticoids (GCs) actions are mostly mediated by the GC receptor (GR), a member of the nuclear receptor superfamily. Alterations of the GR activity have been associated to different diseases including mood disorders. FKBP51 is a GR chaperone that has gained much attention because it is a strong inhibitor of GR activity. FKBP51 exerts effects on many stress-related pathways and may be an important mediator of emotional behavior. Key proteins involved in the regulation of the stress response and antidepressant action are regulated by SUMOylation, a post-translational modification that has an important role in the regulation of neuronal physiology and disease...

SUMOylation is an evolutionarily conserved eukaryotic posttranslational protein modification with broad biological relevance. Differentiating between the major small ubiquitin-like modifier (SUMO) paralogs and uncovering paralog-specific functions in vivo has long been very difficult. To overcome this problem, we generated His6 -HA-Sumo2 and HA-Sumo2 knockin mouse lines, expanding upon our existing His6 -HA-Sumo1 mouse line, to establish a "toolbox" for Sumo1-Sumo2 comparisons in vivo. Leveraging the specificity of the HA epitope, we performed whole-brain imaging and uncovered regional differences between Sumo1 and Sumo2 expression...