The Larimore Lab
The BLOC-1 (Biogenesis of Lysosome Related Organelles Complex 1) is implicated in neurodevelopmental disorders including Autism Spectrum Disorders (ASDs) such as Rett syndrome (RTT) and Schizophrenia (SZ), which have well-documented effects 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 and its role in GABAergic interneuron development.
Research Project: BLOC-1-dependent trafficking mechanisms regulate neurite outgrowth similar to alterations observed in MeCP2 altered cells.
Rett syndrome (RTT) 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 RTT. 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 RTT, overlap with the genetic etiology of major psychoses, such as SZ. However, there are no known molecular mechanisms unifying RTT’s autistic features, SZ, and defective synaptic function.
We propose that the SZ 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 necessary for proper synaptic function and structure. The DTNBP1 gene is among the strongest genes implicated in SZ. 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 and their expression is reduced in the brains of patients with SZ. 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 subunit mRNAs are altered in the hypothalami from mouse models of RTT.
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 neurite 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.