AAV-Mediated Gene Transfer of WDR45 Corrects Neurological Deficits in the Mouse Model of Beta-Propeller Protein-Associated Neurodegeneration.

Beta-propeller protein-associated neurodegeneration (BPAN) is an ultra-rare, X-linked dominant, neurodevelopmental, and neurodegenerative disease caused by loss-of-function mutations in the gene. It manifests in neurodevelopmental delay and seizures followed by secondary neurological decline with dystonia/parkinsonism and dementia in adolescence and early adulthood and is characterized by progressive accumulation of iron in the basal ganglia. encodes β-propeller-shaped scaffold protein, or WD repeat domain phosphoinositide-interacting protein 4 (WIPI4), which plays an important role in autophagosome formation.

Mutation in leads to early motor dysfunction and widespread aberrant axon terminals in a beta-propeller protein associated neurodegeneration (BPAN) patient-inspired mouse model.

Beta-propeller Protein Associated Neurodegeneration (BPAN) is a devastating neurodevelopmental and neurodegenerative disease linked to variants in . Currently, there is no cure or disease altering treatment for this disease. This is, in part, due to a lack of insight into early phenotypes of BPAN progression and 's role in establishing and maintaining neurological function.

A conserved molecular logic for neurogenesis to gliogenesis switch in the cerebral cortex.

During development, neural stem cells in the cerebral cortex, also known as radial glial cells (RGCs), generate excitatory neurons, followed by production of cortical macroglia and inhibitory neurons that migrate to the olfactory bulb (OB). Understanding the mechanisms for this lineage switch is fundamental for unraveling how proper numbers of diverse neuronal and glial cell types are controlled. We and others recently showed that Sonic Hedgehog (Shh) signaling promotes the cortical RGC lineage switch to generate cortical oligodendrocytes and OB interneurons.

Sortilin inhibition treats multiple neurodegenerative lysosomal storage disorders.

Lysosomal storage disorders (LSDs) are a genetically and clinically diverse group of diseases characterized by lysosomal dysfunction. Batten disease is a family of severe LSDs primarily impacting the central nervous system. Here we show that AF38469, a small molecule inhibitor of sortilin, improves lysosomal and glial pathology across multiple LSD models.

Early postnatal administration of an AAV9 gene therapy is safe and efficacious in CLN3 disease.

CLN3 disease, caused by biallelic mutations in the gene, is a rare pediatric neurodegenerative disease that has no cure or disease modifying treatment. The development of effective treatments has been hindered by a lack of etiological knowledge, but gene replacement has emerged as a promising therapeutic platform for such disorders. Here, we utilize a mouse model of CLN3 disease to test the safety and efficacy of a cerebrospinal fluid-delivered AAV9 gene therapy with a study design optimized for translatability.

Breasi-CRISPR: an efficient genome-editing method to interrogate protein localization and protein-protein interactions in the embryonic mouse cortex.

In developing tissues, knowing the localization and interactors of proteins of interest is key to understanding their function. Here, we describe the Breasi-CRISPR approach (Brain Easi-CRISPR), combining Easi-CRISPR with in utero electroporation to tag endogenous proteins within embryonic mouse brains. Breasi-CRISPR enables knock-in of both short and long epitope tag sequences with high efficiency.

Transmembrane Batten Disease Proteins Interact With a Shared Network of Vesicle Sorting Proteins, Impacting Their Synaptic Enrichment.

Batten disease is unique among lysosomal storage disorders for the early and profound manifestation in the central nervous system, but little is known regarding potential neuron-specific roles for the disease-associated proteins. We demonstrate substantial overlap in the protein interactomes of three transmembrane Batten proteins (CLN3, CLN6, and CLN8), and that their absence leads to synaptic depletion of key partners (i.e.

Orexin 1 Receptor Antagonism in the Basolateral Amygdala Shifts the Balance From Pro- to Antistress Signaling and Behavior.

Background: Stress produces differential behavioral responses through select molecular modifications to specific neurocircuitry elements. The orexin (Orx) system targets key components of this neurocircuitry in the basolateral amygdala (BLA).

Methods: We assessed the contribution of intra-BLA Orx receptors (OrxRs) in the expression of stress-induced phenotypes of mice.

Ariadne's Thread in the Developing Cerebral Cortex: Mechanisms Enabling the Guiding Role of the Radial Glia Basal Process during Neuron Migration.

Radial neuron migration in the developing cerebral cortex is a complex journey, starting in the germinal zones and ending in the cortical plate. In mice, migratory distances can reach several hundreds of microns, or millimeters in humans. Along the migratory path, radially migrating neurons slither through cellularly dense and complex territories before they reach their final destination in the cortical plate.

AAV9 Gene Therapy Increases Lifespan and Treats Pathological and Behavioral Abnormalities in a Mouse Model of CLN8-Batten Disease.

CLN8 disease is a rare form of neuronal ceroid lipofuscinosis caused by biallelic mutations in the CLN8 gene, which encodes a transmembrane endoplasmic reticulum protein involved in trafficking of lysosomal enzymes. CLN8 disease patients present with myoclonus, tonic-clonic seizures, and progressive declines in cognitive and motor function, with many cases resulting in premature death early in life. There are currently no treatments that can cure the disease or substantially slow disease progression.

Learning and CRF-Induced Indecision during Escape and Submission in Rainbow Trout during Socially Aggressive Interactions in the Stress-Alternatives Model.

Socially stressful environments induce a phenotypic dichotomy of coping measures for populations in response to a dominant aggressor and given a route of egress. This submission- (Stay) or escape-oriented (Escape) dichotomy represents individual decision-making under the stressful influence of hostile social environments. We utilized the Stress-Alternatives Model (SAM) to explore behavioral factors which might predict behavioral phenotype in rainbow trout.