Regulation of dopamine transporter activity by carboxypeptidase E

<p>Abstract</p> <p>Background</p> <p>The dopamine transporter (DAT) plays a critical role in terminating the action of dopamine by rapid reuptake into the presynaptic neuron. Previous studies have revealed that the DAT carboxyl terminus (DAT-CT) can directly interact with other cellular proteins and regulate DAT function and trafficking.</p> <p>Results</p> <p>Here, we have identified that carboxypeptidase E (CPE), a prohormone processing exopeptidase and sorting receptor for the regulated secretory pathway, interacts with the DAT-CT and affects DAT function. Mammalian cell lines coexpressing CPE and DAT exhibited increased DAT-mediated dopamine uptake activity compared to cells expressing DAT alone. Moreover, coexpression of an interfering DAT-CT minigene inhibited the effects of CPE on DAT. Functional changes caused by CPE could be attributed to enhanced DAT expression and subsequent increase in DAT cell surface localization, due to decreased DAT degradation. In addition, CPE association could reduce the phosphorylation state of DAT on serine residues, potentially leading to reduced internalization, thus stabilizing plasmalemmal DAT localization.</p> <p>Conclusion</p> <p>Taken together, our results reveal a novel role for CPE in the regulation of DAT trafficking and DAT-mediated DA uptake, which may provide a novel target in the treatment of dopamine-governed diseases such as drug addiction and obesity.</p

The risk of infections for multiple sclerosis and neuromyelitis optica spectrum disorder disease-modifying treatments: Eighth European Committee for Treatment and Research in Multiple Sclerosis Focused Workshop Review. April 2021

Over the recent years, the treatment of multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) has evolved very rapidly and a large number of disease-modifying treatments (DMTs) are now available. However, most DMTs are associated with adverse events, the most frequent of which being infections. Consideration of all DMT-associated risks facilitates development of risk mitigation strategies. An international focused workshop with expert-led discussions was sponsored by the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and was held in April 2021 to review our current knowledge about the risk of infections associated with the use of DMTs for people with MS and NMOSD and corresponding risk mitigation strategies. The workshop addressed DMT-associated infections in specific populations, such as children and pregnant women with MS, or people with MS who have other comorbidities or live in regions with an exceptionally high infection burden. Finally, we reviewed the topic of DMT-associated infectious risks in the context of the current SARS-CoV-2 pandemic. Herein, we summarize available evidence and identify gaps in knowledge which justify further research

Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria

The 2010 McDonald criteria for the diagnosis of multiple sclerosis are widely used in research and clinical practice. Scientific advances in the past 7 years suggest that they might no longer provide the most up-to-date guidance for clinicians and researchers. The International Panel on Diagnosis of Multiple Sclerosis reviewed the 2010 McDonald criteria and recommended revisions. The 2017 McDonald criteria continue to apply primarily to patients experiencing a typical clinically isolated syndrome, define what is needed to fulfil dissemination in time and space of lesions in the CNS, and stress the need for no better explanation for the presentation. The following changes were made: in patients with a typical clinically isolated syndrome and clinical or MRI demonstration of dissemination in space, the presence of CSF-specific oligoclonal bands allows a diagnosis of multiple sclerosis; symptomatic lesions can be used to demonstrate dissemination in space or time in patients with supratentorial, infratentorial, or spinal cord syndrome; and cortical lesions can be used to demonstrate dissemination in space. Research to further refine the criteria should focus on optic nerve involvement, validation in diverse populations, and incorporation of advanced imaging, neurophysiological, and body fluid markers

Myelin-oligodendrocyte glycoprotein antibody-associated disease

Myelin-oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a recently identified autoimmune disorder that presents in both adults and children as CNS demyelination. Although there are clinical phenotypic overlaps between MOGAD, multiple sclerosis, and aquaporin-4 antibody-associated neuromyelitis optica spectrum disorder (NMOSD) cumulative biological, clinical, and pathological evidence discriminates between these conditions. Patients should not be diagnosed with multiple sclerosis or NMOSD if they have anti-MOG antibodies in their serum. However, many questions related to the clinical characterisation of MOGAD and pathogenetic role of MOG antibodies are still unanswered. Furthermore, therapy is mainly based on standard protocols for aquaporin-4 antibody-associated NMOSD and multiple sclerosis, and more evidence is needed regarding how and when to treat patients with MOGAD

The risk of infections for multiple sclerosis and neuromyelitis optica spectrum disorder disease-modifying treatments: Eighth European Committee for Treatment and Research in Multiple Sclerosis Focused Workshop Review. April 2021

reserved49: Over the recent years, the treatment of multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) has evolved very rapidly and a large number of disease-modifying treatments (DMTs) are now available. However, most DMTs are associated with adverse events, the most frequent of which being infections. Consideration of all DMT-associated risks facilitates development of risk mitigation strategies. An international focused workshop with expert-led discussions was sponsored by the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and was held in April 2021 to review our current knowledge about the risk of infections associated with the use of DMTs for people with MS and NMOSD and corresponding risk mitigation strategies. The workshop addressed DMT-associated infections in specific populations, such as children and pregnant women with MS, or people with MS who have other comorbidities or live in regions with an exceptionally high infection burden. Finally, we reviewed the topic of DMT-associated infectious risks in the context of the current SARS-CoV-2 pandemic. Herein, we summarize available evidence and identify gaps in knowledge which justify further research.mixedTur, Carmen; Dubessy, Anne-Laure; Otero-Romero, Susana; Amato, Maria Pia; Derfuss, Tobias; Di Pauli, Franziska; Iacobaeus, Ellen; Mycko, Marcin; Abboud, Hesham; Achiron, Anat; Bellinvia, Angelo; Boyko, Alexey; Casanova, Jean-Laurent; Clifford, David; Dobson, Ruth; Farez, Mauricio F; Filippi, Massimo; Fitzgerald, Kathryn C; Fonderico, Mattia; Gouider, Riadh; Hacohen, Yael; Hellwig, Kerstin; Hemmer, Bernhard; Kappos, Ludwig; Ladeira, Filipa; Lebrun-Frénay, Christine; Louapre, Céline; Magyari, Melinda; Mehling, Matthias; Oreja-Guevara, Celia; Pandit, Lekha; Papeix, Caroline; Piehl, Fredrik; Portaccio, Emilio; Ruiz-Camps, Isabel; Selmaj, Krzysztof; Simpson-Yap, Steve; Siva, Aksel; Sorensen, Per Soelberg; Sormani, Maria Pia; Trojano, Maria; Vaknin-Dembinsky, Adi; Vukusic, Sandra; Weinshenker, Brian; Wiendl, Heinz; Winkelmann, Alexander; Zuluaga Rodas, María Isabel; Tintoré, Mar; Stankoff, BrunoTur, Carmen; Dubessy, Anne-Laure; Otero-Romero, Susana; Amato, Maria Pia; Derfuss, Tobias; Di Pauli, Franziska; Iacobaeus, Ellen; Mycko, Marcin; Abboud, Hesham; Achiron, Anat; Bellinvia, Angelo; Boyko, Alexey; Casanova, Jean-Laurent; Clifford, David; Dobson, Ruth; Farez, Mauricio F; Filippi, Massimo; Fitzgerald, Kathryn C; Fonderico, Mattia; Gouider, Riadh; Hacohen, Yael; Hellwig, Kerstin; Hemmer, Bernhard; Kappos, Ludwig; Ladeira, Filipa; Lebrun-Frénay, Christine; Louapre, Céline; Magyari, Melinda; Mehling, Matthias; Oreja-Guevara, Celia; Pandit, Lekha; Papeix, Caroline; Piehl, Fredrik; Portaccio, Emilio; Ruiz-Camps, Isabel; Selmaj, Krzysztof; Simpson-Yap, Steve; Siva, Aksel; Sorensen, Per Soelberg; Sormani, Maria Pia; Trojano, Maria; Vaknin-Dembinsky, Adi; Vukusic, Sandra; Weinshenker, Brian; Wiendl, Heinz; Winkelmann, Alexander; Zuluaga Rodas, María Isabel; Tintoré, Mar; Stankoff, Brun

The risk of infections for multiple sclerosis and neuromyelitis optica spectrum disorder disease-modifying treatments: Eighth European Committee for Treatment and Research in Multiple Sclerosis Focused Workshop Review. April 2021

Over the recent years, the treatment of multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) has evolved very rapidly and a large number of disease-modifying treatments (DMTs) are now available. However, most DMTs are associated with adverse events, the most frequent of which being infections. Consideration of all DMT-associated risks facilitates development of risk mitigation strategies. An international focused workshop with expert-led discussions was sponsored by the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and was held in April 2021 to review our current knowledge about the risk of infections associated with the use of DMTs for people with MS and NMOSD and corresponding risk mitigation strategies. The workshop addressed DMT-associated infections in specific populations, such as children and pregnant women with MS, or people with MS who have other comorbidities or live in regions with an exceptionally high infection burden. Finally, we reviewed the topic of DMT-associated infectious risks in the context of the current SARS-CoV-2 pandemic. Herein, we summarize available evidence and identify gaps in knowledge which justify further research

Dopamine transporter cell surface localization facilitated by a direct interaction with the dopamine D2 receptor

Altered synaptic dopamine levels have been implicated in several neurological/neuropsychiatric disorders, including drug addiction and schizophrenia. However, it is unclear what precipitates these changes in synaptic dopamine levels. One of the key presynaptic components involved in regulating dopaminergic tone is the dopamine transporter (DAT). Here, we report that the DAT is also regulated by the dopamine D2 receptor through a direct protein–protein interaction involving the DAT amino-terminus and the third intracellular loop of the D2 receptor. This physical coupling facilitates the recruitment of intracellular DAT to the plasma membrane and leads to enhanced dopamine reuptake. Moreover, mice injected with peptides that disrupt D2–DAT interaction exhibit decreased synaptosomal dopamine uptake and significantly increased locomotor activity, reminiscent of DAT knockout mice. Our data highlight a novel mechanism through which neurotransmitter receptors can functionally modulate neurotransmitter transporters, an interaction that can affect the synaptic neurotransmitter levels in the brain