The sigma receptors were classified into sigma-1 and sigma-2 receptor based on their different pharmacological profiles. In the past two decades, our understanding of the biological and pharmacological properties of the sigma-1 receptor is increasing; however, little is known about the sigma-2 receptor. Recently, the molecular identity of the sigma-2 receptor has been identified as TMEM97. Although more and more evidence has showed that sigma-2 ligands have the ability to treat cancer and Alzheimer’s disease (AD), the mechanisms connecting these two diseases are unknown. Data obtained over the past few years from human and animal models indicate that cholesterol homeostasis is altered in AD and cancer, underscoring the importance of cholesterol homeostasis in AD and cancer. In this review, based on accumulated evidence, we proposed that the beneficial roles of sigma-2 ligands in cancer and AD might be mediated by their regulation of cholesterol homeostasis.

Sigma receptors, including Sigma-1 receptors and Sigma-2 receptors, are highly expressed in the CNS. They are intracellular chaperone proteins. Sigma-1 receptors localize mainly at the mitochondria-associated endoplasmic reticulum (ER) membrane (MAM). Upon stimulation, they translocate from MAM to plasma membrane (PM) and nucleus, where they interact with many proteins and ion channels. Sigma-1 receptor could interact with itself to form oligomers, its oligomerization states affect its ability to interact with client proteins including ion channels and BiP. Sigma-1 receptor shows high affinity for many unrelated and structurally diverse ligands, but the mechanism for this diverse drug receptor interaction remains unknown. Sigma-1 receptors also directly bind many proteins including G protein-coupled receptors (GPCRs) and ion channels. In recent years, significant progress has been made in our understanding of roles of the Sigma-1 receptors in normal and pathological conditions, but more studies are still required for the Sigma-2 receptors. The physiological roles of Sigma-1 receptors in the CNS are discussed. They can modulate the activity of many ion channels including voltage-dependent ion channels including Ca 2+ , Na + , K + channels and NMDAR, thus affecting neuronal excitability and synaptic activity. They are also involved in synaptic plasticity and learning and memory. Moreover, the activation of Sigma receptors protects neurons from death via the modulation of ER stress, neuroinflammation, and Ca 2+ homeostasis. Evidences about the involvement of Sigma-1 receptors in Parkinson’s disease (PD) and Major Depressive Disorder (MDD) are also presented, indicating Sigma-1 receptors might be promising targets for pharmacologically treating PD and MDD.

L-DOPA is the criterion standard of treatment for Parkinson disease. Although it alleviates some of the Parkinsonian symptoms, long-term treatment induces L-DOPA–induced dyskinesia (LID). Several theoretical models including the firing rate model, the firing pattern model, and the ensemble model are proposed to explain the mechanisms of LID. The “firing rate model” proposes that decreasing the mean firing rates of the output nuclei of basal ganglia (BG) including the globus pallidus internal segment and substantia nigra reticulata, along the BG pathways, induces dyskinesia. The “firing pattern model” claimed that abnormal firing pattern of a single unit activity and local field potentials may disturb the information processing in the BG, resulting in dyskinesia. The “ensemble model” described that dyskinesia symptoms might represent a distributed impairment involving many brain regions, but the number of activated neurons in the striatum correlated most strongly with dyskinesia severity. Extensive evidence for circuit mechanisms in driving LID symptoms has also been presented. LID is a multisystem disease that affects wide areas of the brain. Brain regions including the striatum, the pallidal–subthalamic network, the motor cortex, the thalamus, and the cerebellum are all involved in the pathophysiology of LID. In addition, although both amantadine and deep brain stimulation help reduce LID, these approaches have complications that limit their wide use, and a novel antidyskinetic drug is strongly needed; these require us to understand the circuit mechanism of LID more deeply.

Background: Alpha and gamma adaptin binding protein p34 (AAGAB) was previously reported as a novel on-treatment biomarker can improve prediction of response to neoadjuvant chemotherapy in breast cancer. However, the expression and prognostic value of AAGAB in breast cancer is unknown, the function of AAGAB in breast cancer remains to be elucidated. Methods: Herein we investigated the role of AAGAB in human breast cancer from the TCGA database, immunohistochemistry, Gene set enrichment analysis (GSEA) and immune infiltration analysis. Results: Increased AABAB expression in breast cancer was significantly associated with age, gender, race, ER status, PR status, N-stage, PAM50 classification and histological type (all p-values<0.05). Kaplan-Meier survival analysis showed that breast cancer patients with AAGAB-high had a worse prognosis than that with AAGAB-low (p=0.005). Univariate analysis using logistic regression revealed that age, pathological stage, and number of lymph nodes were significantly associated with poor overall survival (OS) (all p <0.05). AAGAB expression level was significantly correlated with cell purity, CD8 T cells, macrophages, CD4 T cells and dendritic cells. Functional annotations indicated that AAGAB is involved in the most significant signaling pathways including intra Golgi traffic and peroxisomal lipid metabolism pathways. Conclusions: Our study revealed that elevated AAGAB expression was significantly correlated with aggressive progression, poor survival in breast cancer patients. AAGAB may serve as a new biomarker and potential treatment target in breast cancer.