Overall objectives: This research intends to provide a deeper insight into the functional role of mitochondrial aspartate/glutamate carrier (AGC1) in brain. Since a defect in AGC1 gene causes a novel disease whose major feature is a global cerebral hypomyelination, we intend to explain how AGC activity influences myelin biosynthesis in CNS. Specific aims of this project are: the screening of other patients with AGC1 deficiency; the functional analysis of new mutations in the AGC1 gene; the study of AGC expression pattern in different brain cell types, both in vitro and in vivo; the study of AGC1 activity in different brain cell types and its role in N−acetylaspartate (NAA) synthesis and myelin biosynthesis; and the identification of NAA mitochondrial transporter. Background/rationale: AGC1 is the brain isoform of the mitochondrial aspartate/glutamate carrier. Impaired function of AGC1 in a patient and in KO mice leads to a global loss of white matter in brain. A drastic reduction of aspartate and of the myelin lipid precursor NAA has been observed. AGC1 is probably only expressed in neuronal mitochondria where NAA is very likely formed. The role of AGC1 activity in the modulation of NAA brain content and myelin synthesis is not clear. Myelin biosynthesis occurs uniquely in oligodendrocytes where the expression of AGC isoforms has not yet been elucidated. Description of the project: We plan to screen patients in order to identify new mutations in AGC1; characterize the mutations functionally to elucidate the pathogenic mechanisms of the disease; clarify the function of AGC1 in brain; and characterize AGC activity and expression in various brain cell types. We will also quantify the content of AGC substrates and NAA as well as the activity of enzymes involved in myelin synthesis. To elucidate NAA metabolism in neurons, we also intend to identify protein(s) responsible for the transport of NAA in mitochondria. Anticipated output: The expected results of our project will provide clues to elucidate the pathogenic mechanisms underlying the AGC1−deficiency, thus suggesting new therapeutic approaches for the treatment of this novel neuromuscular disease.
Palmieri F., Zeviani M., Pinton P., Monti B. (In stampa/Attività in corso). Progetto Telethon GGP11139 “Mitochondrial Aspartate/Glutamate Carrier 1 Deficiency: Pathogenetic Mechanisms and Mutational Analysis” (2011-2014).
Progetto Telethon GGP11139 “Mitochondrial Aspartate/Glutamate Carrier 1 Deficiency: Pathogenetic Mechanisms and Mutational Analysis” (2011-2014)
MONTI, BARBARA
In corso di stampa
Abstract
Overall objectives: This research intends to provide a deeper insight into the functional role of mitochondrial aspartate/glutamate carrier (AGC1) in brain. Since a defect in AGC1 gene causes a novel disease whose major feature is a global cerebral hypomyelination, we intend to explain how AGC activity influences myelin biosynthesis in CNS. Specific aims of this project are: the screening of other patients with AGC1 deficiency; the functional analysis of new mutations in the AGC1 gene; the study of AGC expression pattern in different brain cell types, both in vitro and in vivo; the study of AGC1 activity in different brain cell types and its role in N−acetylaspartate (NAA) synthesis and myelin biosynthesis; and the identification of NAA mitochondrial transporter. Background/rationale: AGC1 is the brain isoform of the mitochondrial aspartate/glutamate carrier. Impaired function of AGC1 in a patient and in KO mice leads to a global loss of white matter in brain. A drastic reduction of aspartate and of the myelin lipid precursor NAA has been observed. AGC1 is probably only expressed in neuronal mitochondria where NAA is very likely formed. The role of AGC1 activity in the modulation of NAA brain content and myelin synthesis is not clear. Myelin biosynthesis occurs uniquely in oligodendrocytes where the expression of AGC isoforms has not yet been elucidated. Description of the project: We plan to screen patients in order to identify new mutations in AGC1; characterize the mutations functionally to elucidate the pathogenic mechanisms of the disease; clarify the function of AGC1 in brain; and characterize AGC activity and expression in various brain cell types. We will also quantify the content of AGC substrates and NAA as well as the activity of enzymes involved in myelin synthesis. To elucidate NAA metabolism in neurons, we also intend to identify protein(s) responsible for the transport of NAA in mitochondria. Anticipated output: The expected results of our project will provide clues to elucidate the pathogenic mechanisms underlying the AGC1−deficiency, thus suggesting new therapeutic approaches for the treatment of this novel neuromuscular disease.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
