Astroglial toxicity promotes synaptic degeneration in the thalamocortical circuit in frontotemporal dementia with GRN mutations

Abstract

Mutations in the human Progranulin (GRN) gene are a leading cause of frontotemporal lobar degeneration (FTLD). While previous studies implicate aberrant microglial activation as a diseasedriving factor in neurodegeneration in the thalamocortical circuit in Grn -/mice, the exact mechanism for neurodegeneration in FTLD-GRN remains unclear. By performing comparative single-cell transcriptomics in the thalamus and frontal cortex of Grn -/mice and patients with FTLD-GRN, we have uncovered a highly conserved astroglial pathology characterized by upregulation of gap junction protein GJA1, water channel AQP4, and lipid-binding protein APOE, and downregulation of glutamate transporter SLC1A2 that promoted profound synaptic degeneration across the two species. This astroglial toxicity could be recapitulated in mouse astrocyte-neuron cocultures and by transplanting induced pluripotent stem cell-derived astrocytes to cortical organoids, where Progranulin-deficient astrocytes promoted synaptic degeneration, neuronal stress, and TDP-43 proteinopathy. Together, these results reveal previously unappreciated astroglial pathology as a key mechanism in neurodegeneration in FTLD-GRN.

Glia in FTLD-GRN: from supporting cast to leading role

“…Unlike in mice, the number of synapses was unaffected by GRN -/astrocytes. However, organoids engrafted with GRN -/astrocytes exhibited abnormally large synapses that appeared morphologically similar to those in cortical organoids without astrocytes (10). While this result implied that GRN -/astrocytes microglia emphasized the relevance of these transcriptional changes to disease and prognosis.…”

“…These animals display age-associated learning and memory deficits together with TDP-43 aggregates, neuronal loss, and gliosis in the thalamus and hippocampus (2,4,8,9). In this issue of the JCI, Marsan, et al use NanoString, a single nucleus RNA sequencing (snRNA-Seq) technique, to uncover cell-type specific transcriptional changes in FTLD-GRN human and Grn -/mouse brains (10). In so doing, they present a compelling argument for neuroinflammation and the noncell autonomous contributions of glia to neurodegeneration in FTLD-GRN (Figure 1).…”

“…Previous snRNA-Seq studies of microglia in Grn -/mice demonstrated a mutantspecific transcriptional profile, similar to disease-activated microglia (DAM) profiles seen in Alzheimer's disease and amyotrophic lateral sclerosis (ALS) (8). Marsan and colleagues build upon this work by (a) expanding the cell types assessed to include neurons, astrocytes, and other glial cells; (b) complementing the studies in Grn -/mice with snRNA-Seq of postmortem patient's brain tissue with FTLD-GRN; and (c) independently evaluating the cortex and thalamus from both mouse and human samples (10).…”

“…As focus has shifted to the contributions of glial cells to neurodegeneration, evidence of a role for oligodendroglia has emerged (12). Marsan and colleagues also uncovered a striking enrichment for oligodendroglial DEGs in the human FTLD-GRN thalamus, implying that oligodendrocytes may be substantially affected in disease (10). FTLD-GRN is marked by prominent white matter hyperintensities on brain MRIs, the severity of which correlate with disease progression (13).…”

“…Marsan, et al also unearthed an unanticipated contribution from astrocytes to neurodegeneration in FTLD-GRN. Spe- (10) indicate that GRN deficiency induces downstream changes in all four cell types of the brain. Atrophy, gliosis, neuronal loss, and TDP-43 poteinopathy are prominent in gray matter, evident at both the subcellular and transcriptional levels.…”