Overexpression of the low-density lipoprotein receptor (LDLR) is known to decrease apolipoprotein E (APOE) levels and alleviate amyloid beta (Aβ) pathology. We hypothesized that inhibiting the Inducib Show more
Overexpression of the low-density lipoprotein receptor (LDLR) is known to decrease apolipoprotein E (APOE) levels and alleviate amyloid beta (Aβ) pathology. We hypothesized that inhibiting the Inducible Degrader of LDLR (IDOL), an enzyme that ubiquitinates LDLR for degradation, would increase endogenous LDLR levels and attenuate amyloid pathology. To investigate the cell-type-specific role of IDOL, we generated Idol conditional knockout mice on an Aβ-amyloidosis mouse model and performed biochemical, histological, and multi-omics analyses. We demonstrated that neuronal, but not microglial, Idol deletion reduced amyloid accumulation and altered brain LDLR and APOE levels, indicating the critical role of neuronal IDOL-LDLR in amyloid pathology. In addition, neuronal Idol deletion increased the levels of Reelin receptors important for synaptic function, and single-nuclei RNA sequencing revealed significant changes associated with synaptic organization. Neuronal IDOL, but not microglial IDOL, plays a key role in Alzheimer's disease pathogenesis by regulating the levels of brain APOE receptors. Neuronal, but not microglial, Idol deletion reduces amyloid burden and modulates brain APOE and LDLR levels. Deletion of neuronal Idol increases the levels of APOER2 and VLDLR, the Reelin receptors, in the brain. Single-nuclei RNA sequencing highlights the neuronal IDOL's impact on inhibitory neurons and synaptic organization. Targeting neuronal IDOL may provide multiple therapeutic benefits in Alzheimer's disease by modulating APOE receptors. Show less
RAB3GAP1 is GTPase activating protein localized to the ER and Golgi compartments. In humans, mutations in RAB3GAP1 are the most common cause of Warburg Micro syndrome, a neurodevelopmental disorder as Show more
RAB3GAP1 is GTPase activating protein localized to the ER and Golgi compartments. In humans, mutations in RAB3GAP1 are the most common cause of Warburg Micro syndrome, a neurodevelopmental disorder associated with intellectual disability, microcephaly, and agenesis of the corpus callosum. We found that downregulation of RAB3GAP1 leads to a reduction in neurite outgrowth and complexity in human stem cell derived neurons. To further define the cellular function of RAB3GAP1, we sought to identify novel interacting proteins. We used a combination of mass spectrometry, co-immunoprecipitation and colocalization analysis and identified two novel interactors of RAB3GAP1: the axon elongation factor Dedicator of cytokinesis 7 (DOCK7) and the TATA modulatory factor 1 (TMF1) a modulator of Endoplasmic Reticulum (ER) to Golgi trafficking. To define the relationship between RAB3GAP1 and its two novel interactors, we analyzed their localization to different subcellular compartments in neuronal and non-neuronal cells with loss of RAB3GAP1. We find that RAB3GAP1 is important for the sub-cellular localization of TMF1 and DOCK7 across different compartments of the Golgi and endoplasmic reticulum. In addition, we find that loss of function mutations in RAB3GAP1 lead to dysregulation of pathways that are activated in response to the cellular stress like ATF6, MAPK, and PI3-AKT signaling. In summary, our findings suggest a novel role for RAB3GAP1 in neurite outgrowth that could encompass the regulation of proteins that control axon elongation, ER-Golgi trafficking, as well as pathways implicated in response to cellular stress. Show less