Axonal organelle buildup from loss of AP-4 complex function causes exacerbation of amyloid plaque pathology and gliosis in Alzheimer's disease mouse model.

Lysosomes and related precursor organelles robustly build up in swollen axons that surround amyloid plaques and disrupted axonal lysosome transport has been implicated in worsening Alzheimer's pathology. Our prior studies have revealed that loss of Adaptor protein-4 (AP-4) complex function, linked primarily to Spastic Paraplegia (HSP), leads to a similar build of lysosomes in structures we term "AP-4 dystrophies". Surprisingly, these AP-4 dystrophies were also characterized by enrichment of components of APP processing machinery, β-site cleaving enzyme 1 (BACE1) and Presenilin 2.

Endogenous Protein-Protein Interaction Network of the NPC Cholesterol Transporter 1 in the Cerebral Cortex.

NPC intracellular cholesterol transporter 1 (NPC1) is a multipass, transmembrane glycoprotein mostly recognized for its key role in facilitating cholesterol efflux. Mutations in the gene result in Niemann-Pick disease, type C (NPC), a fatal, lysosomal storage disease. Due to the progressively expanding implications of NPC1-related disorders, we investigated endogenous NPC1 protein-protein interactions in the mouse cortex and human-derived iPSCs neuronal models of the disease through coimmunoprecipitation-coupled with LC-MS based proteomics.

Axonal organelle buildup from loss of AP-4 complex function causes exacerbation of amyloid plaque pathology and gliosis in Alzheimer's disease mouse model.

Lysosomes and related precursor organelles robustly build up in swollen axons that surround amyloid plaques and disrupted axonal lysosome transport has been implicated in worsening Alzheimer's pathology. Our prior studies have revealed that loss of Adaptor protein-4 (AP-4) complex function, linked primarily to Spastic Paraplegia (HSP), leads to a similar build of lysosomes in structures we term "AP-4 dystrophies". Surprisingly, these AP-4 dystrophies were also characterized by enrichment of components of APP processing machinery, β-site cleaving enzyme 1 (BACE1) and Presenilin 2.

Prenatal stress and fluoxetine exposure in mice differentially affect repetitive behaviors and synaptic plasticity in adult male and female offspring.

Autism spectrum disorder (ASD) is characterized by social communication impairments with restricted and repetitive behaviors (RRBs). The increase in prevalence of ASD and the heterogeneity of symptom severity may arise from a complex interaction of environmental and genetic factors that alter synaptic plasticity. Maternal stress during pregnancy, which is linked to depression, may be one risk factor for an ASD phenotype in offspring.

AP-4 regulates neuronal lysosome composition, function, and transport via regulating export of critical lysosome receptor proteins at the trans-Golgi network.

The adaptor protein complex-4 or AP-4 is known to mediate autophagosome maturation through regulating sorting of transmembrane cargo such as ATG9A at the Golgi. There is a need to understand AP-4 function in neurons, as mutations in any of its four subunits cause a complex form of hereditary spastic paraplegia (HSP) with intellectual disability. While AP-4 has been implicated in regulating trafficking and distribution of cargo such as ATG9A and APP, little is known about its effect on neuronal lysosomal protein traffic, lysosome biogenesis, and function.

Lysosome Function and Dysfunction in Hereditary Spastic Paraplegias.

Hereditary Spastic Paraplegias (HSPs) are a genetically diverse group of inherited neurological diseases with over 80 associated gene loci. Over the last decade, research into mechanisms underlying HSPs has led to an emerging interest in lysosome dysfunction. In this review, we highlight the different classes of HSPs that have been linked to lysosome defects: (1) a subset of complex HSPs where mutations in lysosomal genes are causally linked to the diseases, (2) other complex HSPs where mutation in genes encoding membrane trafficking adaptors lead to lysosomal defects, and (3) a subset of HSPs where mutations affect genes encoding proteins whose function is primarily linked to a different cellular component or organelle such as microtubule severing and Endoplasmic Reticulum-shaping, while also altering to lysosomes.