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Glial Toxicity in Neurodegeneration: Is There a General Principle?

Weekly Seminar | Not Open to the Public
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Mutations in human progranulin (GRN) gene cause frontotemporal lobar degeneration (FTLD), characterized by TDP-43 protein aggregates in neuronal cytoplasm and dendrites. However, the disease mechanism caused by GRN mutations remains poorly understood. Using Grn knockout (Grn-/-) mice and the GrnR493X knock-in mice, we have previously shown that progranulin deficiency causes age-dependent microglial activation, preferential elimination of inhibitory synapses in the ventral thalamus, and hyperexcitability in the thalamocortical circuits and obsessive-compulsive disorder-like grooming behaviors. In our ongoing work, we use single cell RNA-seq to further characterize the precise timing of transcriptomic and functional changes in Grn-/- microglia and Grn-/- astrocytes in the aging process. Surprisingly, this approach reveals previously unrecognized vulnerability of excitatoryneurons that are selectively eliminated toward disease end-stage. Consistent with these results, in vitro assays show that Grn- /- astrocytes promote synaptic dysfunctions, whereas Grn-/- microglia promote TDP-43 accumulation in neuronal cytoplasm and dendrites, and cell death in excitatory neurons. These results delineate the contributions of glial pathology to neuronal vulnerability in neurodegeneration caused by progranulin deficiency. Whether the same glial toxicity is applicable to other neurodegenerative diseases remains an area of active investigation in my lab.

Eric Huang, Ph.D. Figure


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Progranulin Deficiency Promotes Circuit-Specific Synaptic Pruning by Microglia via Complement Activation.
Cell. 2016 May 5;165(4):921-35. doi: 10.1016/j.cell.2016.04.001. Epub 2016 Apr 21.
Kao AW, McKay A, Singh PP, Brunet A, Huang EJ.
Progranulin, lysosomal regulation and neurodegenerative disease.
Nat Rev Neurosci. 2017 Jun;18(6):325-333. doi: 10.1038/nrn.2017.36. Epub 2017 Apr 24.
Nguyen AD, Nguyen TA, Zhang J, Devireddy S, Zhou P, Karydas AM, Xu X, Miller BL, Rigo F, Ferguson SM, Huang EJ, Walther TC, Farese RV Jr.
Murine knockin model for progranulin-deficient frontotemporal dementia with nonsense-mediated mRNA decay.
Proc Natl Acad Sci U S A. 2018 Mar 20;115(12):E2849-E2858. doi: 10.1073/pnas.1722344115. Epub 2018 Mar 6.


Tuesday, May 7, 2019 - 12:30pm


785 Mamaroneck Avenue
White Plains, NY 10605
United States
Conference Room: 
Billings Building – Rosedale

More Information

Lindsey Echevarria

Conditions & Recovery

Neurodegenerative Diseases icon
Worldwide, 50 million people are living with Alzheimer's and other dementias.