Introduction
Transmembrane protein family members (TMEMs) are a class of proteins that cross biofilms, typically located in the lipid bilayer of the plasma membrane. Some TMEMs are also found in the membranes of organelles such as mitochondria, endoplasmic reticulum, lysosomes, and Golgi bodies. TMEMs are classified into α-helical proteins and β-barrel proteins based on their structural characteristics, which depend on the location of their N-terminal and C-terminal domains. These proteins are present in various cell types and are crucial in numerous physiological processes, including ion channel transport, signal transduction, cellular chemotaxis, adhesion, apoptosis, and autophagy.
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Fig. 1 TMEM-mediated molecular mechanisms in neurological diseases not involving tumors (Chen Q., et al. 2021).
TMEMs in Neurological Disorders
Recent studies have highlighted significant differences in TMEM expression in various neurological diseases. We will summarize the roles of specific TMEMs in neurological diseases like anxiety, phobias, depressive disorders, autism, motor learning disorders, aggressive behavior, hyperlocomotion, cobblestone lissencephaly, neural stem cell (NSC) differentiation, traumatic brain injury (TBI), neuropathic pain, frontotemporal degeneration, and spinocerebellar ataxia type 21.
TMEMs in Psychiatric Disorders
Anxiety disorders are characterized by excessive fear and involve key brain regions such as the amygdala, hippocampus, nucleus accumbens, periaqueductal gray matter, and prefrontal cortex. TMEM16B, a calcium-activated chloride channel (CaCC), is expressed in the central lateral amygdala (CeL), which contains GABAergic inhibitory neurons. Abnormal GABAergic neurotransmission is linked to anxiety. Studies have shown that TMEM16B regulates Ca2+ levels, influencing anxiety-related behavior and fear memory. Knockout of TMEM16B increases GABAergic inhibitory postsynaptic currents, reducing fear- and anxiety-related behaviors by modulating synaptic inhibition in CeL neurons.
The nucleus accumbens (NAc) is crucial in anxiety-related signal transduction. Overexpression of TMEM168 in NAc neurons disrupts GABAergic signaling, leading to anxiety-related behaviors. Diazepam, an antianxiety drug, can reverse these effects, highlighting TMEM168's role in anxiety by affecting GABA neurotransmission and extracellular GABA levels in NAc.
TMEM132D and TMEM132E, located on chromosome 17q11.2-q12, are associated with panic disorders. High expression of TMEM132D in the anterior cingulate cortex (ACC) correlates with increased anxiety levels. TMEM132D influences neuronal signaling by connecting extracellular mediators with the intracellular actin cytoskeleton, affecting the transmission of panic-related behaviors. These findings suggest that TMEM132D and TMEM132E play significant roles in the development of panic disorders.
TMEMs in Depressive Disorders
Depression, a common mental disorder affecting over 350 million people globally, has a lifetime prevalence of up to 20%. The Flinders Depression Sensitive (FSL) rats, a model for human depression, exhibit many depressive-like behaviors. Genome-wide expression profiles of the hippocampus (HIP) and prefrontal/frontal cortex (P/FC) in these rats show significant differences in TMEM176A expression compared to Flinders Depression Resistant (FRL) rats. TMEM176A expression is nearly undetectable in FSL rats but highly expressed in the cortex and hippocampus of FRL rats. These findings indicate that TMEM176A may be a therapeutic target for treating depression.
TMEMs in Autism
TMEM187, located on the X chromosome, interacts with known autism-related genes such as HCFC1, TMLHE, MeCP2, and GPHN. These interactions suggest that TMEM187 influences autism mechanisms. Mutations in TMEM187 are associated with structural changes in proteins, impacting autism development. This gene's interaction with other autism-related genes highlights its potential role in the disorder's pathology.
TMEMs in Motor and Behavioral Disorders
The inferior olivary (IO) neurons in the cerebellum, involved in motor learning, express TMEM16B-CaCC, which influences the excitability of these neurons. TMEM16B-CaCC regulates the firing pattern of IO neurons, essential for cerebellar motor learning. Knockout of TMEM16B reduces the discharge of IO neurons, impairing motor learning ability in mice.
The lateral septum (LS) is associated with aggression. TMEM16B, expressed in hippocampal-LS synapses, regulates neurotransmitter release and excitatory postsynaptic potential (EPSP) in LS neurons. In TMEM16B knockout mice, increased neurotransmitter release in the hippocampal-LS synapse triggers aggressive behavior by altering LS neuronal activity.
The nucleus accumbens (NAc), part of the reward system, is sensitive to external stimuli like methamphetamine. Overexpression of TMEM168 in NAc neurons affects dopaminergic activity and OPN expression, influencing methamphetamine-induced behavioral changes. TMEM168 modulates OPN via DA-mediated functioning of NAc neurons, affecting methamphetamine-induced hyperactivity and addiction.
TMEMs in Developmental Disorders
Cobblestone lissencephaly, a genetic disorder, involves abnormal glucose metabolism affecting brain development. TMEM5 mutations are found in families with this disorder. TMEM5 encodes a glycosyltransferase involved in antiglycoscan glycosylation. Mutations in TMEM5 disrupt glucose metabolism, leading to severe brain abnormalities. These findings highlight TMEM5's importance in brain development and its potential as a therapeutic target.
TMEMs in Neural Stem Cell Differentiation
Neural stem cells (NSCs) can differentiate into various cell types, and miRNAs regulate this process. miRNA-351, by targeting TMEM59, induces morphological changes and promotes NSC differentiation. Overexpression of miRNA-351 decreases TMEM59 expression, accelerating NSC differentiation into neurons and glial cells. This regulation suggests TMEM59 as a potential target for NSC-based therapies.
TMEMs in Traumatic Brain Injury
Traumatic brain injury (TBI) causes cell necrosis and apoptosis. TMEM97 expression, influenced by DKR-1677 treatment, reduces apoptosis and promotes cell survival by maintaining lysosome and mitochondria stability. TMEM97 also regulates cholesterol homeostasis, crucial for cell function and survival. These findings suggest that TMEM97 is a potential therapeutic target for TBI treatment.
Conclusion
TMEMs play diverse and crucial roles in various neurological disorders. From regulating neurotransmitter release and synaptic activity to influencing genetic pathways and cell differentiation, TMEMs are integral to understanding and potentially treating these disorders. Future research should focus on elucidating the precise mechanisms of TMEMs in neurological diseases, aiming to develop targeted therapies that could mitigate the impact of these conditions on patients' lives.
Reference
- Chen Q., et al. Roles, molecular mechanisms, and signaling pathways of TMEMs in neurological diseases. American Journal of Translational Research. 2021, 13(12): 13273.
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