Biology subjects

Yearout, D.

Publications and source records attributed to Yearout, D..

2 recordsLinked to original sources

bioRxiv2026

GBA1 deficiency differentially affects endolysosomal trafficking in neurons versus astrocytes

Mutations in the gene glucosidase, beta acid 1 (GBA1) are the strongest genetic risk factor for Parkinsons disease (PD) and are associated with faster disease progression. GBA1 is expressed in all cell types of the central nervous system, with some evidence supporting higher expression in glial cells than neurons. To elucidate possible specific functions in neurons versus glia, we differentiated human induced pluripotent stem cells (iPSCs) generated from an individual with PD heterozygous for the GBA1 pathogenic null variant IVS2+1 (GBA1IVS/+), homozygous GBA1 IVS2+1 isogenic to GBA1IVS/+ (GBA1IVS/IVS) and a healthy unaffected age-and sex-matched individual (GBA1+/+). GBA1 expression was reduced in GBA1IVS/+ and GBA1IVS/IVS neurons and astrocytes. Endolysosomal trafficking was significantly altered in GBA1-deficient neurons with enlarged early and recycling endosome and lysosome compartments in neurons but not in astrocytes. High molecular weight oligomerization of -synuclein and phosphorylated Ser129 -synuclein were present in GBA1IVS/+ and GBA1IVS/IVS neurons but not in GBA1+/+ neurons, or in GBA1-deficient or GBA1+/+ astrocytes. Transcriptomic analysis of GBA1-deficient neurons and astrocytes revealed cell-type specific profiles. GBA1 deficiency in neurons downregulated immune response and upregulated cholesterol synthesis pathways, while GBA1 deficiency in astrocytes downregulated genes associated with translation and upregulated genes involved in extracellular matrix biogenesis. Transcriptomic analysis also suggests that GBA1 deficiency induces neurotoxic reactivity in astrocytes. Together, these findings indicate that GBA1 deficiency has cell type-specific effects, with increased neuronal vulnerability to endolysosomal trafficking leading to -synucleinopathy while GBA1 deficiency in astrocytes leads to increased neurotoxic reactivity independent of endolysosomal trafficking and -synucleinopathy. HighlightsO_LIiPSC-derived neurons and astrocytes modeled GBA1 deficiency C_LIO_LIEndolysosomal trafficking defects occurred only in GBA1-deficient neurons C_LIO_LI-synuclein oligomers accumulated in GBA1-deficient neurons, not astrocytes C_LIO_LIAstrocyte GBA1 loss drove neurotoxic reactive gene signatures C_LIO_LIGBA1 deficiency causes cell-type specific pathology C_LI

neuroscience↗

bioRxiv2022

Homozygous CADPS2 mutations cause neurodegenerative disease with Lewy bodies in parrots

BackgroundSeveral genetic models that recapitulate neurodegenerative features of Parkinsons disease (PD) exist, which have been largely based on genes discovered in monogenic PD families. However, spontaneous genetic mutations have not been linked to the pathological hallmarks of PD in non-human vertebrates. ObjectiveTo describe the genetic and pathological findings of three yellow crowned parrot (Amazona ochrocepahala) siblings with a severe and rapidly progressive neurological phenotype. MethodsThe phenotype of the three parrots included severe ataxia, head tilt, and stargazing, while their parents were phenotypically normal. Tests to identify avian viral infections and brain imaging studies were all negative. Due to their inability to survive independently, they were all euthanized at age 3 months and their brains underwent neuropathological examination and proteasome activity assays. Whole genome sequencing (WGS) was performed on the three affected parrots and their parents. ResultsThe brains of affected parrots exhibited neuronal loss, spongiosis, and Lewy bodies in the neocortex, amygdala, hypothalamus, periaqueductal gray matter, dorsal vagal nucleus, in some cerebellar Purkinje cells, and in the basal ganglia. Proteasome activity was significantly reduced in the affected parrots compared to a control (p<0.05). WGS identified a single homozygous missense mutation (p.V559L) in a highly conserved amino acid residue within the pleckstrin homology (PH) domain of the Calcium Dependent Secretion Activator 2 (CADPS2) gene. Previous studies suggest that CADPS2 is expressed at high levels in the substantia nigra where it regulates BDNF release. Thus, disruption of CADPS2 function could impact survival of dopaminergic neurons. Furthermore, CADPS2 expression is in part regulated by two well established PD genes, LRRK2 and SNCA. ConclusionsOur data suggest that a homozygous mutation in the CADPS2 gene causes a severe neurodegenerative phenotype with Lewy bodies in parrots. Although CADPS2 variants have not been reported to cause PD in humans, further investigation of the gene in model organisms might provide important insights into the pathophysiology of Lewy body disorders.

neuroscience↗