Translational Neurodegeneration, Journal Year: 2025, Volume and Issue: 14(1)

Published: April 16, 2025

Abstract Heterozygous mutations in GRN gene lead to insufficient levels of the progranulin (PGRN) protein, resulting frontotemporal dementia (FTD) with TAR DNA-binding protein 43 (TDP-43) inclusions, classified pathologically as lobar degeneration (FTLD-TDP). Homozygous are exceedingly rare and cause neuronal ceroid lipofuscinosis 11, a lysosomal storage disease onset young adulthood, or an FTD syndrome late-onset manifestations. In this review, we highlight broad spectrum clinical phenotypes associated PGRN deficiency, including primary progressive aphasia behavioral variant dementia. We explore these alongside relevant rodent vitro human models, ranging from induced pluripotent stem cell-derived neural progenitors, neurons, microglia, astrocytes genetically engineered heterotypic organoids containing both neurons astrocytes. summarize advantages limitations models recapitulating main FTLD- hallmarks, highlighting role non-cell-autonomous mechanisms formation TDP-43 pathology, neuroinflammation, neurodegeneration. Data obtained patients’ brain tissues biofluids, parallel single-cell transcriptomics, demonstrate complexity interactions among highly heterogeneous cellular clusters present brain, astrocytes, oligodendroglia, endothelial cells, pericytes. Emerging evidence has revealed that deficiency is cell cluster-specific, often conserved, genetic molecular central nervous system. focus on how distinct populations their dysfunctional crosstalk contribute neurodegeneration neuroinflammation FTD- . Specifically, characterize lipid droplet-accumulating microglia alterations myelin content dysfunction caused by deficiency. Additionally, consider deregulation glia-neuron communication affects exchange organelles such mitochondria, removal excess toxic products aggregates, PGRN-related

Language: Английский