IBBR Project #92
MOLECULAR AND CELLULAR UNDERPINNINGS OF THE NEUROLOGICAL PHENOTYPES ASSOCIATED TO MITOCHONDRIAL CITRATE CARRIER (SLC25A1) DEFICIENCY
| Project ID | 92 |
| ID | GEP1414 |
| Acronym | GEP1414 |
| Project acronym and title | MOLECULAR AND CELLULAR UNDERPINNINGS OF THE NEUROLOGICAL PHENOTYPES ASSOCIATED TO MITOCHONDRIAL CITRATE CARRIER (SLC25A1) DEFICIENCY |
| Contract | - |
| Description | Broad objectives and specific aims We aim to investigate the mechanisms through which alterations in SLC25A1,encoding for the mitochondrial citrate carrier (CiC),cause the associated neurological phenotypes with a particular emphasis on the molecular and cellular underpinnings of the observed neuromuscular junction (NMJ) defects. Background/Rationale Our own previous work indicate that the severity of clinal phenotype is inversely correlated with residual transport activity. Mild phenotypes present the characteristic clinical features of congenital myasthenic syndromes. Preliminary data from a morpholino knockdown zebrafish model point towards an underlying presynaptic defect. Signal transmission at the neuromuscular junction relies on massive synthesis of the (Ach) from choline and acetylCoA. While the former can be recycled after neurotransmitter release and breackdown, the latter must be continuously generated by oxidative metabolism in mitochondria from which it is exported in the form of citrate by the CiC. We hypothesize that SLC25A1 deficiency impinges on Ach synthesis and MNJ transmission. A defect in lipid biosythesis may also play role in the more severe phenotypes. Research design and methods for achieving the stated objectives We will obtain motor neurons and myotubes from inducible Pluripotent Stem cells derived from fibroblasts of two patients with different neurological presentations but both with documented NMJ defects. Molecular and cellular parameters, and in particular Ach synthesis and the cholinergic transmission will be investigated. A lipidomics analysis will also be performed. Furthermore, we will exploit C. elegans powerful genetics as well as the vast toolbox of manipulations and in vivo observations available, to generate and characterize an animal model of th e disease. Anticipated output Our studies will provide new models to investigate the neurological phenotypes associated to SLC25A1 deficiency and new knowledge on MNJ transmission |
| Funding body | FONDAZIONE TELETHON |
| UOS | Napoli |
| Role | Collaborazione |
| Signatory | Palmieri Luigi |
| Contact Person | Di Schiavi Elia |
| Starting of activities | 2015 |
| Ending of activities | 2016 |
| Extension | - |
| Amount (euro) | 13000.00 |
| Technological Area | - |
| Technological Field | Basi molecolari e cellulari della vita degli organismi |
