AAV-GRN subunit injections can rescue FTD disease phenotypes Público

Abstract

Frontotemporal dementia (FTD) is the most common cause of dementia in those under the age of 60. FTD is characterized by the neurodegeneration of the frontal and temporal lobes and can cause behavioral disinhibition, apathy, or difficulty speaking or understanding language. There is no treatment for the underlying cause of FTD. One cause of FTD is heterozygous mutations of the granulin (GRN) gene which leads to haploinsufficiency of the progranulin (PGRN) protein and its granulin subunits. While the precise function of PGRN and granulins are unknown, prior research has shown that disease phenotypes of FTD-like mice can be rescued using adeno-associated virus (AAV) encoding PGRN. However, AAV-PGRN may not be a viable clinical therapy because PGRN is a pleiotropic protein and administration of AAV-PGRN to the brain is challenging. Thus, granulin subunits have become proteins of interest in the disease pathology of FTD-GRN. While the full function of granulin subunits in the disease pathology of FTD-GRN is unknown, prior research has hypothesized that granulin subunits may be toxic or harmful. This study aims to understand if AAV constructs of granulin subunits will exacerbate or rescue disease phenotypes in the hippocampus of FTD-like mice. This study found the first evidence that granulin subunits can rescue disease phenotypes in an in vivo model of FTD.

Table of Contents

Frontotemporal Dementia (FTD)…………………………………………………………….1

Progranulin and its subunits…………………………………………………………………4

Granulin subunits……………………………………………………………………………..5

Lysosomal dysfunction in FTD………………………………………………………………7

Markers of lysosomal dysfunction…………………………………………………………..8

Gliosis and inflammation in FTD……………………………………………………………10

Markers of gliosis and inflammation………………………………………………………..11

Pre-clinical mice model of FTD……………………………………………………………..12

AAV-Grn injections rescue function………………………………………...………………13

Methods………………………………………………………………………………………..14

Results………………………………………………………………………………………....16

Discussion…………………………………………………………………………………...…26

Conclusion……………………………………………………………………………………...30

Supplemental Figures and Tables………………………………………………………...…32

References……………………………………………………………………………………..34

About this Honors Thesis

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School	Emory College
Department	Neuroscience and Behavioral Biology
Degree	B.S.
Submission	Honors Thesis
Language	English
Research Field	Biology, Neuroscience
Palabra Clave	Granulin
Committee Chair / Thesis Advisor	Dr. Thomas Kukar, Emory University
Committee Members	Dr. Chad Hales, Emory University Dr. Kristen Frenzel, Emory University

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