The Roles Of NEDD4 Subfamily Of HECT E3 Ubiquitin Ligases in Neurodevelopment And Neurodegeneration Part 2

The HECT, C2, and WW domains containing E3 ubiquitin protein ligase 1 (HECW1) and 2 (HECW2), also known as NEDD4-like ubiquitin protein ligase 1 (NEDL1) or 2 (NEDL2), are the most recently discovered members in the NEDD4 subfamily. 

With the continuous development of biotechnology, people are increasingly interested in the relationship between cellular proteins and memory. Research shows that protein is the most basic biomolecule in cells and plays an important role in various tissues and organs of the human body, and its impact on memory cannot be ignored.

Proteins exist in various forms in the human body, the most important of which are neuronal proteins. Neuronal proteins are a class of proteins that exist in large amounts within neurons and are an important component of neuronal activity. Research shows there is a strong connection between neuronal proteins and memory. The synthesis and degradation of neuronal proteins are the basis for memory. Only when the protein synthesis rate in the cell is faster than the degradation rate in this process can good memories be formed and maintained. Therefore, maintaining the stability of neuronal proteins is crucial for people's memory.

In addition to neuronal proteins, other proteins in the body can affect memory. For example, ATP-dependent protein kinase (AMPK) in the cellular energy metabolism pathway is a key regulator of intracellular energy metabolism. Studies have shown that promoting the activity of AMPK can increase the rate of protein synthesis in brain tissue, thereby improving memory.

At the same time, consuming some foods rich in high-quality protein in the human body can also promote the rate of protein synthesis in cells, thereby improving memory. For example, protein-rich fish, meat, eggs, and other foods can provide high-quality protein to the human body.

To sum up, there is a close connection between cellular proteins and memory. Maintaining the stability of neuronal proteins and promoting the protein synthesis rate in cells is very important for improving people's memory. We should pay attention to diet, eat foods rich in high-quality protein, and strengthen physical exercise to increase cell metabolism speed, which will help improve our memory level. It can be seen that we need to improve memory, and Cistanche deserticola can significantly improve memory, because Cistanche deserticola has antioxidant, anti-inflammatory, and anti-aging effects, which can help reduce oxidation and inflammatory reactions in the brain, thereby protecting the health of the nervous system. In addition, Cistanche deserticola can also promote the growth and repair of nerve cells, thus enhancing the connectivity and function of neural networks. These effects can help improve memory, learning, and thinking speed, and may also prevent the development of cognitive dysfunction and neurodegenerative diseases.

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Functional studies on these two proteins are just beginning. NEDL1 is involved in the Wnt signaling pathway by ubiquitination and degradation of Dishevelled-1 (Dvl1) [5,52,53]. 

Recent findings support that NEDL1 is also implicated in the TGF-β signaling pathway by ubiquitination of Smad4 [54]. These two proteins, HECW1 and HECW2, seem to interfere with various physiological mechanisms such as the enteric nervous system and kidney development [55,56]. 

As described above, the NEDD4 E3 ligases subfamily can be regulated in various ways. These enzymes can bind to various proteins via interactions with their three domains, leading to positive or negative regulation. An example of positive regulation is the action of adaptor proteins, such as Smads, that facilitate the binding of subs the rates of the TGF-beta pathway on the two SMURF proteins, NED, D4-2, WWP1, and ITCH ligases. [47,57–61]. 

NEDD4 family inproteinsng protein 1 and 2 (NDFIP1 and NDFfacilitateacilitates the action of ITCH and NEDD4-1 [62,63]. WW linkers peptides, small sequences between two WW regions, interact with the HECT catalytic domain in these E3 ligases, leading to self-regulation of the NEDD4 subfamily proteins. These interactions prevent the activity of the catalytic domain and sometimes drive autoubiquitination [64]. 

NEDD4 subfamily members can also be regulated by post-translational modifications. We have already mentioned phosphorylation for NEDD4-2, for example. Studies also observed SUMOylation of SMURF2, and neddylation of SMURF ligases, I, TCH, NEDL1, and NEDL2 [65].

4. NEDD4 E3 Ligases in Neurodevelopment

Many studies support that E3 ubiquitin ligases play crucial roles in CNS development, from the proliferation of stem cells and progenitors to neuronal differentiation, maturation, and functioning [2,66]. 

NEDD4 subfamily members appear to be actively involved in these various stages of CNS development. The first stage of CNS development is the proliferation of undifferentiated brain cells. Several cell signaling pathways are strongly involved in this stage, such as the bone morphogenetic protein BMP, TGF-β and Wnt signaling pathways, all of which are regulated in part by the HECT E3 SMURF1 and SMURF2, as described above [48,57,67]. 

NEDD4-1 is known to promote cell proliferation [68], as is WWP2, whose silencing significantly reduces the cell proliferation rate in vitro [69]. NEDD4-1 binds, by its third WW domain, the non-canonical sequence (non-PY motif) of FGFR1, resulting in its ubiquitination [70]. 

The FGF/FGFR1 (fibroblast growth factor/receptor 1) signaling pathway consists of another important pathway for CNS development. It is necessary for hippocampal growth in the CNS, for example, because it promotes the proliferation of hippocampal progenitors and stem cells during development in mice [71]. Maintenance of the neural stem cell pool and self-renewal also requires the Hedgehog signaling pathway. 

The Hedgehog transcription factor Gli1 is targeted by the protein Numb for ITCH-dependent ubiquitination, which suppresses the Hedgehog signal [72]. It is interesting to note that truncating mutations in ITCH have been identified in children with multisystem autoimmune diseases, dysmorphic features, relative mac, microcephaly, and neurodevelopmental abnormalities including developmental delay and cognitive impairment [73]. 

The second stage of CNS development consists of migration of the cells in the brain and spinal cord, and their differentiation into specific types of neurons and glial cells. WWP1 and WWP2 knockout results in axon defects–dendrite polarity in pyramidal neurons and aberrant laminar cortical distribution showing that these NEDD4-like E3 ligases are essential for proper polarization of developing neurons [74]. 

SMURF1, by regulation of the Rho GTPase, promotes neurite outgrowth [75]. Moreover, its phosphorylation on Threonine 306 by the protein kinase A promotes axon formation. Preventing this phosphorylation results in altered polarization in cortical neurons in vivo [76]. 

NEDD4- 1/small GTPase Rap2A signaling pathway regulates neurite growth and arborization in neurons [77]. NEDD4-2 also promotes axonal growth [78]. Genetic variants in NEDD4-2 have been observed in patients with periventricular nodular heterotopia, polymicrogyria, macrocephaly, cleft palate, and syndactyly [79], suggesting a role for NEDD4-2 in neuronal migration. 

HECW2 consists of another important NEDD4 HECT E3 ligase in neurodevelopment. It stabilizes p73, [80] a crucial factor for neurogenesis and neurodevelopment. Mice lacking p73 expression show severe neurodevelopmental abnormalities with hippocampal dysgenesis [81]. Recently, de novo mutations in the HECW2 gene have been identified in patients with neurodevelopmental diseases, including epilepsy, intellectual d, efficiency, and macrocephaly [82–85]. 

The third stage of CNS development involves the formation of innumerable connections among neurons, both within and across regions. Phosphatase and tensin homolog (PTEN) is a known target of NEDD4-1 for ubiquitination, followed by degradation. 

The interaction between PTEN and NEDD4-1 seems to be implicated in the building of synaptic connections. NEDD4-1 is expressed in Xenopus retinal ganglion cells, where dysfunction of the E3 ligase leads to severe inhibition of terminal branching. This inhibition is thought to be caused by the downregulation of PTEN mediated by NEDD4-1. Indeed, decreasing PTEN in dysfunctional NEDD4-1 cells rescued branching defects [86]. 

Interestingly, it was also shown that NEDD4-1 ubiquitinated AMPA receptors, promoting their endocytosis [87]. A recent study associated polymorphic hisms in the NEDD4-1 gene with schizophrenia and cognitive dysfunction [88]. NEDD4-2 is called the E3 ligase of ion channels and transporters because it has been shown that, in Xenopus oocytes, it strongly inhibits the activity of several Nav channels. 

In cortical neurons, it controls the intracellular concentration of sodium by acting on voltage-gated channels. This was demonstrated in fetal cortical neurons from NEDD4-2 deficient mice [89]. A study in humans suggested the role of the NEDD4-2 gene in photosensitive generalized epilepsy, but this remains to be proven [90]. Overall, to date, three genes of the NEDD4 E3 ligases family (IT, CH, HECW2, and NEDD4-2) have been related to syndromic neurodevelopmental disorders. 

Interestingly, aside from neurodevelopmental features, macrocephaly appears to be a constant clinical manifestation. Of note, macrocephaly has also been observed in neurodevelopmental disorders related to other E3 ligase-encoding genes such as HUWE1 [91]. 

As mentioned above, E3 ligases interact with PTEN and other proteins involved in the PI3K-AKT-mTOR signaling pathway. Pathogenic variants in several genes of this pathway lead to overgrowth syndromes with neurodevelopmental disorders and macrocephaly [92].

5. NEDD4 E3 Ligases in Neurodegeneration

More and more evidence indicates that the defectubiquitin-proteasomeroteasome pathinitiatesiate or contributes to the worsening of neurodegeneration in various neurodegenerative diseases. 

Exploring the roles of HECT E3 ligases (proteins highly expressed in neurons and participating in processes involved in neurodegeneration, such as protein aggregation, oxidative, apoptosis, and abnormalities in glutamatergic transmission) has become important. Protein aggregate formation is considered to be directly involved in the pathophysiology of many neurodegenerative diseases. 

Researchers have cited the aggregation of TDP-43 proteins in Amyotrophic Lateral Sclerosis (ALS), amyloiAlzheimer's Alzheimer's disease (AD), α-synParkinson's disease (PD), or polyglutamine-expanded Huntingtin pHuntington'sHuntington disease (HD) [93–95], for example. NEDD4-1 is implicated in targeting α-synuclein to the endosomal compartment and in lysosomal degradation of α-synuclein [96,97]. 

It has also been shown to protect against α-synuclein-induced toxicity in Drosophila and in rodent models of PD. Overexpression of NEDD4-1 in Drosophila brain rescue α-synuclein-induced locomotor defects [98]. 

Moreover, NEDD4-1 is implicated in Amyloid-β peptide regulation through P-glycoprotein ubiquitination [99]. A role for ITCH has also been indicated in several neurodegenerative diseases. 

It is found in polyglutamine-expanded huntingtin of ataxin-3 perinuclear aggregates and interacts with them. Its overexpression reduces aggregation of misfolded protein in cells under stress conditions [100]. ITCH, such as WWP1, another NEDD4 E3, interaSpartinhSpartinn, a protein encoded by the SPG20 gene which is mutated in an autosomal recessive form of hereditary spastic paraplegia [15]. 

ITCH, WWP1, as well as NEDL1, ubiquitinate and allow degradation of ErbB4 protein in a cell model of breast cancer [101]. Mutations in the ErbB4 gene, encoding a member of the epidermal growth factor receptor, disrupt the Neuregulin-ErbB4 pathway, causing Amyotrophic Lateral Sclerosis (ALS), a neurodegenerative disease characterized by the loss of upper and lower motor neurons [102]. 

Neurodegenerating motor neurons in ALS display TDP-43 positive aggregates containing the HECT E3 SMURF2 and some of its substrates, Smad2/3 [103]. NEDL1 was also associated with ALS caused by the action of the Superoxide Dismutase 1 (SOD1) gene. 

It was described as an E3 ubiquitin ligase, able to ubiquitinate and mediate proteasomal degradation of mutanwild-typeot wildtype, SOD1 proteins [53]. Interestingly, mice over the pressing of the human HECW1 gene encoding NEDL1 showed motor neuron degeneration and muscle atrophy, as observed in ALS [104].

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