The Larimore Lab
The BLOC-1 (Biogenesis of Lysosome Related Organelles Complex 1) is implicated in neurodevelopment disorders including Autism Spectrum Disorders (ASDs) such as Rett Syndrome (RTT) and Schizophrenia (SZ), all of which have well-documented affects on neuronal morphology in the hippocampus and the cortex. BLOC-1 regulates vesicle trafficking from early endosomes to late endosomes and in neurons, it regulates trafficking from the cell body to the synaptic terminal. BLOC-1 may regulate the trafficking of integral membrane proteins that regulate neuronal differentiation. Currently, the lab is exploring the role of BLOC-1 in neuronal differentiation and branching as that could directly impact function of parvalbumin interneurons in the hippocampus.
Research Project: BLOC-1-dependent trafficking mechanisms regulate neuritis outgrowth similar to alterations observed in MeCP2 altered cells.
Rett syndrome is a severe neurodevelopmental disorder with autistic features that results from mutations in the MECP2 gene, which is located on the X-chromosome. A prevailing hypothesis is that synaptic function is altered in Rett syndrome. However, the precise cellular and molecular mechanisms underlying synaptic defects observed in this disease are not completely understood. Epidemiological genetics indicates that genetic factors contributing to autistic phenotypes, such as those observed in Rett syndrome, overlap with the genetic etiology of major psychoses, such as schizophrenia. However, there are no molecular mechanisms unifying Rett Syndrome’s autistic features, schizophrenia, and defective synaptic function. In this application, we propose that the schizophrenia susceptibility factor, dysbindin (encoded by the DTNBP1 locus) and its interacting proteins, define a pathway controlled by MeCP2 that regulates vesicle traffic to the synapse.
The DTNBP1 gene is among the strongest genes associated with schizophrenia risk. DTNBP1 encodes dysbindin, a protein that form part of a protein complex, the dysbindin-BLOC-1 complex. Subunits of this complex, pallidin and dysbindin, are targeted to the synapse (Larimore & Faundez, unpublished results) and their expression is reduced in the brain of schizophrenia patients. We demonstrated that the dysbindin-BLOC-1 complex participates in the generation of vesicle carriers that deliver synaptic membrane proteins from cell body endosomes to nerve terminals. Furthermore, we have established that synaptic expression of dysbindin-BLOC-1 complex subunits is drastically reduced in synapses of Mecp2 mutant mice determined by quantitative confocal and immuno-electron microscopy. Our findings are further supported by the observation that the expression of dysbindin-BLOC-1 subunits mRNAs is altered in the hypothalami from mouse models of Rett syndrome. These fundamental observations lead us to hypothesize that impaired dysbindin-BLOC-1-dependent vesicle traffic to the synapse contributes to the synaptic phenotypes observed in MeCP2 null mice.
Currently, we are comparing neuritis outgrowth in cells in culture with altered BLOC-1 or MeCP2 content under different variables. Using immunoblotting, confocal microscopy and qt-PCR, we will document these changes.