Dataset Information

AAV-GRN partially corrects motor deficits and ALS/FTLD-related pathology in Tmem106b^-/-Grn^-/- mice.

ABSTRACT: Loss of function of progranulin (PGRN), encoded by the granulin (GRN) gene, is implicated in several neurodegenerative diseases. Several therapeutics to boost PGRN levels are currently in clinical trials. However, it is difficult to test the efficacy of PGRN-enhancing drugs in mouse models due to the mild phenotypes of Grn^-/- mice. Recently, mice deficient in both PGRN and TMEM106B were shown to develop severe motor deficits and pathology. Here, we show that intracerebral ventricle injection of PGRN-expressing AAV1/9 viruses partially rescues motor deficits, neuronal loss, glial activation, and lysosomal abnormalities in Tmem106b^-/-Grn^-/- mice. Widespread expression of PGRN is detected in both the brain and spinal cord for both AAV subtypes. However, AAV9 but not AAV1-mediated expression of PGRN results in high levels of PGRN in the serum. Together, these data support using the Tmem106b^-/-Grn^-/- mouse strain as a robust mouse model to determine the efficacy of PGRN-elevating therapeutics.

SUBMITTER: Feng T

PROVIDER: S-EPMC10371829 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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AAV-GRN partially corrects motor deficits and ALS/FTLD-related pathology in Tmem106b-/-Grn-/- mice.

Feng Tuancheng T Minevich Gregory G Liu Pengan P Qin Henry Xin HX Wozniak Glenn G Pham Jenny J Pham Khanh K Korgaonkar Akshata A Kurnellas Michael M Defranoux Nadine A NA Long Hua H Mitra Ananya A Hu Fenghua F

iScience 20230628 7

Loss of function of progranulin (PGRN), encoded by the granulin (GRN) gene, is implicated in several neurodegenerative diseases. Several therapeutics to boost PGRN levels are currently in clinical trials. However, it is difficult to test the efficacy of PGRN-enhancing drugs in mouse models due to the mild phenotypes of Grn-/- mice. Recently, mice deficient in both PGRN and TMEM106B were shown to develop severe motor deficits and pathology. Here, we show tha ...[more]

PMID: 37519899

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Project description:Human cellular models of neurodegeneration require reproducibility and longevity, which is necessary for simulating age-dependent diseases. Such systems are particularly needed for TDP-43 proteinopathies1, which involve human-specific mechanisms2-5 that cannot be directly studied in animal models. Here, to explore the emergence and consequences of TDP-43 pathologies, we generated induced pluripotent stem cell-derived, colony morphology neural stem cells (iCoMoNSCs) via manual selection of neural precursors6. Single-cell transcriptomics and comparison to independent neural stem cells7 showed that iCoMoNSCs are uniquely homogenous and self-renewing. Differentiated iCoMoNSCs formed a self-organized multicellular system consisting of synaptically connected and electrophysiologically active neurons, which matured into long-lived functional networks (which we designate iNets). Neuronal and glial maturation in iNets was similar to that of cortical organoids8. Overexpression of wild-type TDP-43 in a minority of neurons within iNets led to progressive fragmentation and aggregation of the protein, resulting in a partial loss of function and neurotoxicity. Single-cell transcriptomics revealed a novel set of misregulated RNA targets in TDP-43-overexpressing neurons and in patients with TDP-43 proteinopathies exhibiting a loss of nuclear TDP-43. The strongest misregulated target encoded the synaptic protein NPTX2, the levels of which are controlled by TDP-43 binding on its 3' untranslated region. When NPTX2 was overexpressed in iNets, it exhibited neurotoxicity, whereas correcting NPTX2 misregulation partially rescued neurons from TDP-43-induced neurodegeneration. Notably, NPTX2 was consistently misaccumulated in neurons from patients with amyotrophic lateral sclerosis and frontotemporal lobar degeneration with TDP-43 pathology. Our work directly links TDP-43 misregulation and NPTX2 accumulation, thereby revealing a TDP-43-dependent pathway of neurotoxicity.

Dataset Information

AAV-GRN partially corrects motor deficits and ALS/FTLD-related pathology in Tmem106b^-/-Grn^-/- mice.

Publications

AAV-<i>GRN</i> partially corrects motor deficits and ALS/FTLD-related pathology in <i>Tmem106b</i><sup><i>-/-</i></sup><i>Grn</i><sup><i>-/-</i></sup> mice.

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