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Review
. 2023 Jan 14:19:133-151.
doi: 10.2147/NDT.S376380. eCollection 2023.

Endo-Lysosomal and Autophagy Pathway and Ubiquitin-Proteasome System in Mood Disorders: A Review Article

Petala Matutino Santos  1 , Giovanna Pereira Campos  1 , Camila Nascimento  2
Affiliations
Review

Endo-Lysosomal and Autophagy Pathway and Ubiquitin-Proteasome System in Mood Disorders: A Review Article

Petala Matutino Santos et al. Neuropsychiatr Dis Treat. .

Abstract

Mood disorders are disabling conditions that cause significant functional impairment. Due to the clinical heterogeneity and complex nature of these disorders, diagnostic and treatment strategies face challenges. The etiology of mood disorders is multifactorial, involving genetic and environmental aspects that are associated with specific biological pathways including inflammation, oxidative stress, and neuroprotection. Alterations in these pathways may reduce the cell's ability to recover from stress conditions occurring during mood episodes. The endo-lysosomal and autophagy pathway (ELAP) and the ubiquitin-proteasome system (UPS) play critical roles in protein homeostasis, impacting neuroplasticity and neurodevelopment. Thus, emerging evidence has suggested a role for these pathways in mental disorders. In the case of neurodegenerative diseases (NDDs), a deeper understanding in the role of ELAP and UPS has been critical to discover new treatment targets. Since it is suggested that NDDs and mood disorders share clinical symptomatology and risk factors, it has been hypothesized that there might be common underlying molecular pathways. Here, we review the importance of the ELAP and UPS for the central nervous system and for mood disorders. Finally, we discuss potential translational strategies for the diagnosis and treatment of major depressive disorder and bipolar disorder associated with these pathways.

Keywords: autophagy; endo-lysosomal pathway; endo-lysosome; mood disorders; neuroplasticity; novel treatments; translational science; treatment target; ubiquitin-proteasome system.

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Conflict of interest statement

The authors report no conflicts of interest in this work.

Figures

Figure 1
Figure 1
The endo-lysosomal and autophagy pathway. The process of endocytosis is regulated by a Rab GTPase called rab5, which helps with protein internalization and endosome maturation, trafficking, and signaling. Once the early endosome is formed, the process of maturation continues, the rab5-to-rab7 conversion underlies the cargo transition from early to late endosomes/ MVBs. This process is also mediated by mitochondria, which send MDVs for the formation of MVBs. The endocytic pathway has two main routes: either the MVBs can fusion with autophagosomes, together with lysosomes leading to the autophagic process; or merge to the plasma membrane and release their vesicles into the extracellular space, which will later be called exosomes.
Figure 2
Figure 2
Protein quality control systems are activated upon the occurrence of unfolded proteins. The UPR acts in three ways: (A) increasing the transcription of chaperones; (B) inhibiting translation; (C) positively regulating ERAD components.
Figure 3
Figure 3
UPR’s mechanisms of action. In stress situations, PERK and IRE1α proteins dissociate from the GRP78 chaperone, autophosphorylates, form dimers, and phosphorylate other proteins. PERK phosphorylates eIF2-α, causing attenuation of protein translation. When the levels of eIF2-α are limited, ATF4 mRNA is translated and up-regulates CHOP, which responds to induce apoptosis. IRE1α activates XBP1 mRNA splicing, thus inducing the expression of chaperones.
Figure 4
Figure 4
The ubiquitin-proteasome pathway. The ubiquitin (Ub) binds to E1, and it is activated (aUb). Then it is transferred to E2. The complex (E2 + aUb) binds to E3 and then aUb connects to the target protein. Other monomers bind to aUb, forming a polyubiquitinated chain, which serves as a signal for degradation. If the linkage involves lysine-63, degradation occurs through the lysosome, whereas if the linkage involves lysine-48, degradation is dependent on the 26S proteasome. The deubiquitination enzymes (DUBs) remove the substrate from the protein, before being degraded.
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