The Roles Of NEDD4 Subfamily Of HECT E3 Ubiquitin Ligases in Neurodevelopment And Neurodegeneration Part 3

Oxidative stress and activation of apoptotic pathways are involved in the pathophysiology of many neurodegenerative diseases. 

The relationship between oxidative stress and memory has attracted widespread attention from scholars. Oxidative stress is an inevitable physiological phenomenon in living organisms. It is caused by the excessive production of free radicals, oxygen ions, and other oxidative substances in the body, which leads to an imbalance in the redox state within the body, thereby causing oxidative damage to biological macromolecules, cell membranes, etc. It ultimately May impair various physiological functions, including memory. However, the latest research shows that appropriate oxidative stress has a good effect on promoting memory.

First, oxidative stress can activate the antioxidant defense mechanism in brain cells, promote their metabolism, and enhance the viability and adaptability of nerve cells.

Secondly, moderate oxidative stress can also promote the synthesis of beneficial substances in brain cells and improve the connection and stability of nerve cells. For example, the continuous synthesis of beneficial substances such as antioxidant enzymes and heat shock proteins will improve the self-repair ability of neurons, thereby enhancing learning and memory functions.

Finally, oxidative stress can also activate some genes related to cell survival and differentiation, promote cell regeneration and renewal, and thus be of great benefit in promoting cognitive ability and memory.

In short, moderate oxidative stress can help improve cognition and memory abilities and should be taken seriously and used rationally. However, it needs to be emphasized that excessive oxidative stress is not good for health. Therefore, you should consume more antioxidants in your daily diet, while also paying attention to reducing the occurrence of chronic diseases and maintaining a healthy lifestyle. It can be seen that we need to improve memory, and Cistanche deserticola can significantly improve memory, because Cistanche deserticola can also regulate the balance of neurotransmitters, such as increasing the levels of acetylcholine and growth factors. These substances are very important for memory and learning. In addition, Cistanche deserticola can also improve blood flow and promote oxygen delivery, which can ensure that the brain receives sufficient nutrients and energy, thereby improving brain vitality and endurance.

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Oxidative stress produces reactive radical oxygen species (ROS), which trigger the expression of pro-apoptotic factors. Alzheimer's disease (AD), PD, and ALS have been associated with impaired insulin/insulin growth factor (IGF)-1 signaling [105]. 

IGF-1 degradation is mediated by the ubiquitin-proteasome system (UPS), and NEDD4-1 plays a key role in this process. NEDD4-1 is upregulated by a variety of neurotoxins that elicit oxidative stress in neurons, leading to IGF-1 degradation by the UPS. An elevated NEDD4-1 expression was found in brain tissues of AD, PD, and HD patients, and also in the spinal cord tissues of ALS patients and mutant SOD1 mice. 

Downregulation/inactivation of NEDD4-1 rescued neurons from death mediated by zinc toxicity [106]. NEDD4-1 has also been associated with other proteins that are particularly important in the regulation of cellular stress response (HSF-1) and apoptosis (NDFIP1). 

Heat Shock Transcription Factor-1 (HSF-1) is a master stress transcription factor that activates gene encoding for chaperones and anti-apoptotic proteins. Its dysregulation is thought to be implicated in neurodegeneration, especially in α-synucleinopathy. Under proteotoxic stress conditions induced by α-Synuclein, NEDD4-1 is the E3 ligase in neurons that ubiquitinates HSF-1 for further degradation by the proteasome. 

Aberrant degradation of HSF-1 involving NEDD4-1 could be an important molecular key mechanism underlying α-synucleinopathy and extensive neurodegeneration [107]. NEDD4-1 also interacts with NDFIP1 (NEDD4 family interacting protein), a transmembrane protein with a protective role in a cell model of PD, helping reduce apoptosis and improving cell survival rate. This binding generates enhanced expression of NDFIP1 [108]. 

Loss of NEDD4-1 has been associated with the elevation of RTP801, a pro-apoptotic protein sufficient and necessary to induce neuronal death in cellular and animal models of PD [109]. SMURF1 and SMURF2 are other HECT E3 ligases with links to apoptotic pathways. 

SMURF1 has been described as a Hirano Body (HB)-associated protein [110]. HB was first observed in patients suffering from ALS and PD, and then in AD. SMURF1 is upregulated by pro-inflammatory cytokines playing a role in apoptosis in CNS injury [111]. 

It has also been shown to inhibit p53-mediated apoptosis by stabilizing the MDM2-MDMX complex that ubiquitinates p53 leading to its degradation [51]. SMURF2 has been described as a negative regulator of TGF-β signaling, a major actor in apoptosis regulation. 

Treatment with the carbamate pesticide, carbofuran, leads to neurodegeneration by increased TGF-β signaling with a significant SMURF2 downregulation [112]. TGF-β signaling is increased, especially in AD, PD, and ALS patients [113]. 

Another major factor in apoptosis is the p53 protein. p53-mediated apoptosis has been directly involved in processes leading to neurodegeneration. Interestingly, the HECT E3 NEDL1 enhances p53-mediated apoptosis [114]. 

Glutamate is the most abundant excitatory neurotransmitter in the central nervous system. In AD, cognitive decline is due to synaptic impairment caused by the cleavage of the amyloid precursor protein into the pathogenic peptide amyloid-β (Aβ) [115]. Aβ decreases the subtype of ionotropic glutamate receptor AMPA-R at the membrane. 

The precise molecular mechanisms leading to this decrease remain unclear; however, in cultured neurons with Aβ-induced synaptic dysfunction, a role for ubiquitination mediated by NEDD4-1 on AMPA-R was identified. 

NEDD4-1 is known to target AMPA-R and Aβ promotes its recruitment, thus increasing ubiquitination and degradation of the synaptic receptors [116]. The HECT E3 NEDD4-2 is implicated in the ubiquitination and degradation of BEST1 (bestrophin-1), a calcium-activated chloride channel expressed at the surface of neurons and astrocytes [117]. 

BEST1 is implicated in glutamate and GABA release, associated with modulating neuronal excitability and synaptic transmission under pathological conditions such as neuroinflammation and neurodegeneration. 

Another link has been extensively described between glutamate and neurodegenerative diseases: glutamate excitotoxicity. Excessive glutamate in synapses is toxic and has been linked to AD, ALS, and HD. Dysfunctional glutamate transporters contribute to this excitotoxicity [118]. 

The HECT E3 NEDD4-2 can mediate the ubiquitination of glutamate transporters in vitro and in vivo models of PD [119]. In MPP+ (1-methyl-4-phenylpyridinium) treated astrocytes, ubiquitinated (Ub) glutamate transporters GLT-1 levels are increased while non-Ub GLT-1 levels are reduced. 

This is reversed by siRNA-mediated knockdown of NEDD4-2. Similar results were obtained in the MPTP mouse model of PD (1-methyl-4-phenyl-1,2,2,6-tetrahydropyridine). Knockdown of NEDD4-2 in this mouse model resulted in an improvement in movement disorders [120].

6. Conclusions and Future Perspectives

The ubiquitin pathway is a major factor in the regulation of protein homeostasis and the activity of many proteins. The deregulation of this pathway, composed of many enzymes and particularly E3 ligases, leads to defects in neuronal development and function, causing neurodevelopmental or neurodegenerative diseases (Figure 3). 

In this work, we have provided the first review of the functions and regulation of a particular subfamily of E3 ligases highly expressed in the brain, the NEDD4 subfamily of E3 HECT ubiquitin ligases. It is the best-characterized subgroup of the 28 HECT-type enzymes [121]. 

The 9 members of this NEDD4 subfamily have been highly conserved during evolution in mammals, but also in non-mammals, such as Caenorhabditis elegans or Drosophila. Proteins sharing the same structures and domains as NEDD4 proteins have been found in yeast Saccharomyces cerevisiae and Schizosaccharomyces pombe [17].

E3 enzymes of the NEDD4 subfamily are known to be highly expressed in the CNS. 

Recent studies indicate that they have diverse and important roles in the development and function of neurons. They also participate in the cellular processes involved in the regulation of cell survival and programmed cell death (Figure 3). 

Genetic studies have shown that some of the genes encoding these enzymes are mutated in particular neurodevelopmental and neurodegenerative diseases. It is very likely that further genetic studies, using next-generation sequencing on large cohorts of patients, will show the involvement of this E3 family in other CNS pathologies. Neurodegenerative diseases are known to be age-related diseases. 

Age can lead to modifications in the concentration and activity of enzymes of the ubiquitin pathway. Changes in activity can be caused by post-translational modifications (PTM) such as deamidation. 

Indeed, deamidation is thought to be a molecular clock for protein turnover and can lead to protein denaturation or aggregation [122]. The effect of deamidation of ubiquitin ligases of the NEDD4 family should be, like phosphorylation, seriously studied. 

The modification of their concentration or activity could affect cellular processes and result in neurodegeneration. The regulatory mechanisms of NEDD4 are quite diversified, as seen previously. This opens interesting opportunities to develop therapeutics that would allow modulation (blocking, decreasing, or increasing) of their actions. 

We could target the protein domains of regulation of the enzymatic activity, such as the HECT enzymatic domain, and the domain of interaction with ligands. Some molecules have been already developed to act on NEDD4 proteins, such as the anticancer drug Bortezomib, which interacts with several proteins of the NEDD4 subfamily [123]. 

Clomipramine, a drug used to treat depression, specifically blocks the HECT catalytic activity of the NEDD4 ITCH [124]. The NEDD4 subfamily has grown to be of great interest to those interested in physiological and pathophysiological processes in the CNS. 

Given the diversity and importance of the functions played by the proteins of this subfamily in neurons and the possibility of developing therapeutics specifically targeting them, further research on these particular ligases is needed.

Author Contributions: Conceptualization, S.H., P.V. and C.R.A.; methodology, S.H., P.V., and C.R.A.; validation, S.H., P.V., and C.R.A.; writing-original draft preparation, S.H., P.V., S.M., C.V.-D., D.L., F.L., P.C., H.B., and C.R.A.; writing-review and editing, S.H., P.V., M.J., S.M., C.V.-D., D.L., F.L., P.C., H.B. and C.R.A.; supervision, P.V. and C.R.A.; project administration, P.V., and C.R.A.; funding acquisition, P.V., and C.R.A. All authors have read and agreed to the published version of the manuscript.

Funding: This research received no external funding.

Institutional Review Board Statement: Not applicable.

Informed Consent Statement: Not applicable.

Data Availability Statement: Not applicable.

Acknowledgments: This research was supported by Inserm the University of Tours, and the foundation ARSLA, France. SH acknowledges financial support from the Region Centre Val de Loire (Fellowship).

Conflicts of Interest: The authors declare no conflict of interest.

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