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Granulins rescue inflammation, lysosome dysfunction, and neuropathology in a mouse model of progranulin deficiency

ABSTRACT: In this study, we investigate whether individual granulin subunits derived from the precursor protein progranulin are beneficial. We test this by asking if delivery of a single granulin to the brains of a preclinical model of FTD-GRN Grn-/-mice is sufficient to ameliorate disease-like phenotypes. We performed intracerebroventricular injections of recombinant adeno-associated virus (rAAV2/1) encoding granulin-2, granulin-4, full-length PGRN or GFP in neonatal Grn+/+ and Grn-/- mice. Following AAV injections, mice were aged for 12 months, tissues collected, and analyzed. Quantitative proteomics of the thalamus identified lysosomal function and neuroinflammation as pathways ameliorated by the expression of granulins. Biochemical markers of lysosomal dysfunction, neuroinflammation, and disease-like pathology were assessed via immunoblot and immunohistochemistry. We found that both granulin-2 and granulin-4 rescue markers of lysosomal dysfunction and neuroinflammation in cortical, hippocampal, and thalamic tissue.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

SUBMITTER: Duc Duong

LAB HEAD: Thomas Kukar

PROVIDER: PXD041095 | Pride | 2024-10-15

REPOSITORIES: Pride

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PROs favor observation of some prostate patients.

Hospital peer review 19950701 7

PMID: 10153205

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