Where More is Less: Lysosomal Dysregulation in Response to PGRN Haploinsufficiency Leads to Upregulated C1qa and Synaptic Pruning in Frontotemporal Lobar Dementia

Jaqueline Stoutin

Introduction. FTLD is a clinically heterogenous disease most often presenting with social disinhibition and apathy (1-5). FTLD is the second leading cause of early-onset dementia after Alzheimer’s Disease. There is currently no treatment for FTLD (1-4). In cases of PGRN haploinsufficiency, there is widespread lysosomal dysregulation: in microglia, there is accumulation of inactive cathepsin pro-forms, while in neurons, higher proteolytic activity of CTSD and LAMP1 are found (6-8). This increases the rate of proteolysis within the endolysosome through upregulation of CD68, which in turn upregulates the compliment pathway via C1qa (8,9). The presence of C1qa is linked to increases in microglial activity and synaptic pruning (8,9). C1qa is translated and secreted at the highest rates in the VPM/VPL (9). Neuronal loss in the VPM/VPL and disrupted myelination in the cerebral cortex lead to symptoms of FTLD9. Restoration of progranulin to normal levels has been achieved with an adeno-associated virus vector (AAV-Grn) to normalize lysosomal activity (10). (Methods. PCR was performed using mRNA from primary cortical neurons and neonatal microglia prepared from Grn+/+ and Grn−/−mice and treated with LPS (50 ng/ml) to show how microglia activation upregulates C1qa mRNA levels (9). Using SPH as a marker for synaptic density, Grn−/− mice showed significant reductions in the ventral thalamus, whereas SPH density in Grn−/−;C1qa−/−mice was almost completely preserved (9). Microgliosis was assessed by CD68 immunoreactivity and the morphology of Iba1+ cells (10). Results. By identifying the essential role of C1qa in mediating synaptic pruning by Grn−/− microglia, complement proteins could serve as biomarkers to distinguish FTLD from AD (9). As these diseases progress, there is a divergence in CSF levels of C1qa: it rises in FTLD and falls in AD9. C1qa levels could help differentiate between these two diagnoses and allow patients to access appropriate treatment (9). With respect to FTLD treatment, AAV-Grn has been found to reduce CTSD activity in Grn−/− mice to levels seen in wild-type mice (10). There is a normalization of postmortem CTSD activity and LAMP-1 levels which indicate a shift toward normal lysosomal homeostasis in AAV-Grn-treated Grn−/− mice. Grn−/− mice also exhibit less microgliosis throughout the brain (10). These data provide in vivo support for the efficacy of progranulin-boosting therapies for FTLD (10). Conclusion. These results suggest that neurodegeneration due to progranulin deficiency may be partially caused by altered lysosome function and subsequent aberrant microglial activation via C1qa deposition. This increased activity results in overly aggressive synapse removal, thus suggesting C1qa plays a crucial role as drivers of neurodegeneration in FTLD.

 

  1. Gotzl JK., Colombo AV., Fellerer K et al. Early lysosomal maturation deficits in microglia triggers enhanced lysosomal activity in other brain cells of progranulin knockout mice. Mol Neurodegeneration. 2018; 13(48). doi: 10.1186/s13024-018- 0281-5
  2. Chitramuthu, B., Bennett, H., Bateman, A. Progranulin: a new avenue towards the understanding and treatment of neurodegenerative disease. Brain. 2017;140(12); 3081–3104. doi: 10.1093/brain/awx198.
  3. Paushter, D.H., Du, H., Feng, T. et al. The lysosomal function of progranulin, a guardian against neurodegeneration. Acta Neuropathologica. 2018;136(1): 1–17. doi: 10.1007/s00401-018-1861-8.
  4. Wauters, E., Van Mossevelde, S., Van der Zee, J., et al. Modifiers of GRNAssociated Frontotemporal Lobar Degeneration. Cell: Trends in Molecular Medicine. 2017; 23(10): 962-979. doi.org/10.1016/j.molmed.2017.08.004.
  5. Tanaka Y, Chambers JK, Matsuwaki T et al. Possible involvement of lysosomal dysfunction in pathological changes of the brain in aged progranulin-deficient mice. Acta Neuropathologica. 2014; 2(78). doi: 10.1186/s40478-014-0078-x.
  6. Nilson, A., English, K., Gerson, J. et al. Tau Oligomers Associate with Inflammation in the Brain and Retina of Tauopathy Mice and in Neurodegenerative Diseases. Journal of Alzheimer’s Disease. 2016; 55(3): 1083-1099. doi: 10.3233/JAD-160912
  7. Kao, A.; McKay, A.; Singh, P. et al. Progranulin, lysosomal regulation and neurodegenerative disease. Nature Neuroscience. 2017; 18(6): 325–333. doi: 10.1038/nrn.2017.36.
  8. Zhou, X., Sun, L., Bracko, O., et al. Impaired prosaposin lysosomal trafficking in frontotemporal lobar degeneration due to progranulin mutations. Nature Communications. 2017; 8(152770). doi: 10.1038/ncomms15277.
  9. Lui, H., Zhang, J., Makinson, S. et al. Progranulin Deficiency Promotes Circuit-Specific Synaptic Pruning by Microglia via Complement Activation. Cell. 2016;165(4): 921-935. doi.org/10.1016/j.cell.2016.04.001.
  10. Arrant AE., Onyilo VC., Unger DE., et al. Progranulin Gene Therapy Improves Lysosomal Dysfunction and Microglial Pathology Associated with Frontotemporal Dementia and Neuronal Ceroid Lipofuscinosis. Journal of Neuroscience. 2018; 38(9): 2341-2358. Doi: https://doi-org.srvproxy2