scholarly journals The Role of Preclinical Models in Creatine Transporter Deficiency: Neurobiological Mechanisms, Biomarkers and Therapeutic Development

Genes ◽  
2021 ◽  
Vol 12 (8) ◽  
pp. 1123
Author(s):  
Elsa Ghirardini ◽  
Francesco Calugi ◽  
Giulia Sagona ◽  
Federica Di Vetta ◽  
Martina Palma ◽  
...  
Keyword(s):  
Current Knowledge ◽  
Human Condition ◽  
Clinical Aspects ◽  
Missense Mutations ◽  
Preclinical Development ◽  
Creatine Transporter Deficiency ◽  
Therapeutic Development ◽  
Transporter Deficiency ◽  
Scientific Challenge ◽  
Slc6a8 Gene

Creatine (Cr) Transporter Deficiency (CTD) is an X-linked metabolic disorder, mostly caused by missense mutations in the SLC6A8 gene and presenting with intellectual disability, autistic behavior, and epilepsy. There is no effective treatment for CTD and patients need lifelong assistance. Thus, the research of novel intervention strategies is a major scientific challenge. Animal models are an excellent tool to dissect the disease pathogenetic mechanisms and drive the preclinical development of therapeutics. This review illustrates the current knowledge about Cr metabolism and CTD clinical aspects, with a focus on mainstay diagnostic and therapeutic options. Then, we discuss the rodent models of CTD characterized in the last decade, comparing the phenotypes expressed within clinically relevant domains and the timeline of symptom development. This analysis highlights that animals with the ubiquitous deletion/mutation of SLC6A8 genes well recapitulate the early onset and the complex pathological phenotype of the human condition. Thus, they should represent the preferred model for preclinical efficacy studies. On the other hand, brain- and cell-specific conditional mutants are ideal for understanding the basis of CTD at a cellular and molecular level. Finally, we explain how CTD models might provide novel insight about the pathogenesis of other disorders, including cancer.

scholarly journals New insights into creatine transporter deficiency

2020 ◽  
Author(s):  
Angelo Molinaro
Keyword(s):  
Neural Circuits ◽  
Neurodegenerative Disorder ◽  
Therapeutic Interventions ◽  
Clinical Aspects ◽  
Progressive Damage ◽  
Compensatory Mechanisms ◽  
Severe Condition ◽  
Brain Functions ◽  
Creatine Transporter Deficiency ◽  
Transporter Deficiency

Creatine (Cr) transporter deficiency (CCDS1) is a very rare and severe condition due to impaired energetic metabolism. In this work we showed for the first time the following facts: this diseases is a progressive neurodegenerative disorder in which a set of maladaptive compensatory mechanisms leads to a progressive damage of brain functions; cell energy metabolism and mitochondria seem strongly involved in the pathogenesis and they could represent useful potential targets for therapeutic interventions; inflammation seems to play an important part in this progressive damage, and this observation can pave the way to treatment strategies; neural circuits disruption involving inhibitory systems could give a huge contribute to many of the clinical aspects observed in patients, as epilepsy and cognitive impairment, since the excitatory/inhibitory balance is fundamental for the normal function of neural circuits. Factors outside the CNS are important in the pathogenesis of at least some aspects of the disorder, since the conditional KO model show difference in the timing of onset of some cognitive defects and in the presence of stereotypies.

scholarly journals Advances in the Regulation of Mammalian Follicle-Stimulating Hormone Secretion

Animals ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 1134
Author(s):  
Hao-Qi Wang ◽  
Wei-Di Zhang ◽  
Bao Yuan ◽  
Jia-Bao Zhang
Keyword(s):  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Follicle Stimulating Hormone ◽  
Hormone Secretion ◽  
Β Subunit ◽  
Glycoprotein Hormone ◽  
Livestock Breeding ◽  
Biological Specificity ◽  
Therapeutic Development ◽  
Stimulating Hormone

Mammalian reproduction is mainly driven and regulated by the hypothalamic-pituitary-gonadal (HPG) axis. Follicle-stimulating hormone (FSH), which is synthesized and secreted by the anterior pituitary gland, is a key regulator that ultimately affects animal fertility. As a dimeric glycoprotein hormone, the biological specificity of FSH is mainly determined by the β subunit. As research techniques are being continuously innovated, studies are exploring the underlying molecular mechanism regulating the secretion of mammalian FSH. This article will review the current knowledge on the molecular mechanisms and signaling pathways systematically regulating FSH synthesis and will present the latest hypothesis about the nuclear cross-talk among the various endocrine-induced pathways for transcriptional regulation of the FSH β subunit. This article will provide novel ideas and potential targets for the improved use of FSH in livestock breeding and therapeutic development.

scholarly journals Clinical Aspects of Substance Abuse in Persons with Schizophrenia

2003 ◽  
Vol 48 (1) ◽  
pp. 14-21 ◽  
Author(s):  
Juan C Negrete
Keyword(s):  
Substance Abuse ◽  
Current Knowledge ◽  
Psychiatric Service ◽  
Psychosocial Interventions ◽  
Clinical Aspects ◽  
Continuing Care ◽  
Self Medication ◽  
Integrated Therapy ◽  
Therapy Services ◽  
Persons With Schizophrenia

Objective: To review the current knowledge on the problem of psychoactive substance abuse by persons with schizophrenia, with particular attention to issues of direct relevance to clinical practice. Method: The author examined the literature from the last 2 decades and data from studies in which he was involved. Results: Schizophrenia sufferers show an elevated liability for substance abuse. Such comorbidity may derive from self-medication attempts, a common neuropathology for addiction and schizophrenia, the psychotogenic properties of certain drugs, or the influence of environmental factors. Among schizophrenia patients receiving treatment, substance misuse is associated with more severe symptoms and poorer therapeutic response. The presence of a chronic psychosis impedes treatment of the substance problem in traditional, nonpsychiatric addiction programs. Better outcomes are observed in integrated therapy services, where patients receive appropriate care for both conditions. Conclusion: Dual-pathology patients need comprehensive care with appropriate pharmacotherapy and psychosocial interventions. This treatment can be best provided within the context of a continuing care psychiatric service.

The clinical syndrome of creatine transporter deficiency

2003 ◽  
pp. 45-48 ◽  
Author(s):  
Ton J. deGrauw ◽  
Kim M. Cecil ◽  
Anna W. Byars ◽  
Gajja S. Salomons ◽  
William S. Ball ◽  
...  
Keyword(s):  
Clinical Syndrome ◽  
Creatine Transporter ◽  
Creatine Transporter Deficiency ◽  
Transporter Deficiency

scholarly journals A novel mouse model of creatine transporter deficiency

F1000Research ◽  
2015 ◽  
Vol 3 ◽  
pp. 228
Author(s):  
Laura Baroncelli ◽  
Maria Grazia Alessandrì ◽  
Jonida Tola ◽  
Elena Putignano ◽  
Martina Migliore ◽  
...  
Keyword(s):  
Mouse Model ◽  
Murine Model ◽  
Deficiency Syndrome ◽  
Speech Impairment ◽  
Behavioral Disturbances ◽  
Creatine Transporter ◽  
Creatine Transporter Deficiency ◽  
Creatine Deficiency ◽  
Creatine Deficiency Syndrome ◽  
Transporter Deficiency

Mutations in the creatine (Cr) transporter (CrT) gene lead to cerebral creatine deficiency syndrome-1 (CCDS1), an X-linked metabolic disorder characterized by cerebral Cr deficiency causing intellectual disability, seizures, movement  and behavioral disturbances, language and speech impairment ( OMIM #300352).CCDS1 is still an untreatable pathology that can be very invalidating for patients and caregivers. Only two murine models of CCDS1, one of which is an ubiquitous knockout mouse, are currently available to study the possible mechanisms underlying the pathologic phenotype of CCDS1 and to develop therapeutic strategies. Given the importance of validating phenotypes and efficacy of promising treatments in more than one mouse model we have generated a new murine model of CCDS1 obtained by ubiquitous deletion of 5-7 exons in the Slc6a8 gene. We showed a remarkable Cr depletion in the murine brain tissues and cognitive defects, thus resembling the key features of human CCDS1. These results confirm that CCDS1 can be well modeled in mice. This CrT−/y murine model will provide a new tool for increasing the relevance of preclinical studies to the human disease.

Sign in / Sign up

Export Citation Format

Share Document