Lysosome and Inflammatory Defects in GBA1-Mutant Astrocytes Are Normalized by LRRK2 Inhibition
| Autor: | Mark P. DeAndrade, Steven C. Lin, Hailey S. Novis, Anwesha Sanyal, Malú G. Tansey, Julianna J. Tomlinson, Matthew J. LaVoie, Jianjun Chang, Nathalie A. Lengacher |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Parkinson's disease Biology medicine.disease_cause Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 Article Pathogenesis 03 medical and health sciences Mice 0302 clinical medicine Lysosome medicine Animals Humans Kinase activity Neuroinflammation Mutation Gaucher Disease Parkinson Disease medicine.disease LRRK2 Cell biology 030104 developmental biology medicine.anatomical_structure Neurology Astrocytes Glucosylceramidase Neurology (clinical) Lysosomes Glucocerebrosidase 030217 neurology & neurosurgery |
| Zdroj: | Mov Disord |
| Popis: | Background Autosomal recessive mutations in the glucocerebrosidase gene, Beta-glucocerebrosidase 1 (GBA1), cause the lysosomal storage disorder Gaucher's disease. Heterozygous carriers of most GBA1 mutations have dramatically increased Parkinson's disease (PD) risk, but the mechanisms and cells affected remain unknown. Glucocerebrosidase expression is relatively enriched in astrocytes, yet the impact of its mutation in these cells has not yet been addressed. Objectives Emerging data supporting non-cell-autonomous mechanisms driving PD pathogenesis inspired the first characterization of GBA1-mutant astrocytes. In addition, we asked whether LRRK2, likewise linked to PD and enriched in astrocytes, intersected with GBA1 phenotypes. Methods Using heterozygous and homozygous GBA1 D409V knockin mouse astrocytes, we conducted rigorous biochemical and image-based analyses of lysosomal function and morphology. We also examined basal and evoked cytokine response at the transcriptional and secretory levels. Results The D409V knockin astrocytes manifested broad deficits in lysosomal morphology and function, as expected. This, however, is the first study to show dramatic defects in basal and TLR4-dependent cytokine production. Albeit to different extents, both the lysosomal dysfunction and inflammatory responses were normalized by inhibition of LRRK2 kinase activity, suggesting functional intracellular crosstalk between glucocerebrosidase and LRRK2 activities in astrocytes. Conclusions These data demonstrate novel pathologic effects of a GBA1 mutation on inflammatory responses in astrocytes, indicating the likelihood of broader immunologic changes in GBA-PD patients. Our findings support the involvement of non-cell-autonomous mechanisms contributing to the pathogenesis of GBA1-linked PD and identify new opportunities to correct these changes with pharmacological intervention. © 2020 International Parkinson and Movement Disorder Society. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|