Modelling TDP-43 proteinopathy in Drosophila uncovers shared and neuron-specific targets across ALS and FTD relevant circuits

Authors

R Keating Godfrey, Department of Molecular and Cellular Biology, Life Sciences South, University of Arizona, 1007 E. Lowell St., Tucson, AZ, 85721, USA. rkeating.godfrey@ufl.edu.
Eric Alsop, Translational Genomics Research Institute, 445 N 5th St., Phoenix, AZ, 85004, USA.
Reed T. Bjork, Department of Molecular and Cellular Biology, Life Sciences South, University of Arizona, 1007 E. Lowell St., Tucson, AZ, 85721, USA.
Brijesh S. Chauhan, Cellular and Molecular Physiology, Penn State College of Medicine, 500 University Drive Crescent Building C4605, Hershey, PA, 17033, USA.
Hillary C. Ruvalcaba, Department of Molecular and Cellular Biology, Life Sciences South, University of Arizona, 1007 E. Lowell St., Tucson, AZ, 85721, USA.
Jerry Antone, Translational Genomics Research Institute, 445 N 5th St., Phoenix, AZ, 85004, USA.
Lauren M. Gittings, Department of Translational Neuroscience, Barrow Neurological Institute, 350 W Thomas Road, Phoenix, AZ, 85013, USA.Follow
Allison F. Michael, Department of Molecular and Cellular Biology, Life Sciences South, University of Arizona, 1007 E. Lowell St., Tucson, AZ, 85721, USA.
Christi Williams, Department of Molecular and Cellular Biology, Life Sciences South, University of Arizona, 1007 E. Lowell St., Tucson, AZ, 85721, USA.
Grace Hala'ufia, Department of Molecular and Cellular Biology, Life Sciences South, University of Arizona, 1007 E. Lowell St., Tucson, AZ, 85721, USA.
Alexander D. Blythe, Department of Molecular and Cellular Biology, Life Sciences South, University of Arizona, 1007 E. Lowell St., Tucson, AZ, 85721, USA.
Megan Hall, Translational Genomics Research Institute, 445 N 5th St., Phoenix, AZ, 85004, USA.
Rita Sattler, Department of Translational Neuroscience, Barrow Neurological Institute, 350 W Thomas Road, Phoenix, AZ, 85013, USA.
Kendall Van Keuren-Jensen, Translational Genomics Research Institute, 445 N 5th St., Phoenix, AZ, 85004, USA.
Daniela C. Zarnescu, Department of Molecular and Cellular Biology, Life Sciences South, University of Arizona, 1007 E. Lowell St., Tucson, AZ, 85721, USA. dcz102@psu.edu.

Document Type

Article

Abstract

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) comprise a spectrum of neurodegenerative diseases linked to TDP-43 proteinopathy, which at the cellular level, is characterized by loss of nuclear TDP-43 and accumulation of cytoplasmic TDP-43 inclusions that ultimately cause RNA processing defects including dysregulation of splicing, mRNA transport and translation. Complementing our previous work in motor neurons, here we report a novel model of TDP-43 proteinopathy based on overexpression of TDP-43 in a subset of Drosophila Kenyon cells of the mushroom body (MB), a circuit with structural characteristics reminiscent of vertebrate cortical networks. This model recapitulates several aspects of dementia-relevant pathological features including age-dependent neuronal loss, nuclear depletion and cytoplasmic accumulation of TDP-43, and behavioral deficits in working memory and sleep that occur prior to axonal degeneration. RNA immunoprecipitations identify several candidate mRNA targets of TDP-43 in MBs, some of which are unique to the MB circuit and others that are shared with motor neurons. Among the latter is the glypican Dally-like-protein (Dlp), which exhibits significant TDP-43 associated reduction in expression during aging. Using genetic interactions we show that overexpression of Dlp in MBs mitigates TDP-43 dependent working memory deficits, conistent with Dlp acting as a mediator of TDP-43 toxicity. Substantiating our findings in the fly model, we find that the expression of GPC6 mRNA, a human ortholog of dlp, is specifically altered in neurons exhibiting the molecular signature of TDP-43 pathology in FTD patient brains. These findings suggest that circuit-specific Drosophila models provide a platform for uncovering shared or disease-specific molecular mechanisms and vulnerabilities across the spectrum of TDP-43 proteinopathies.

Keywords

ALS, Drosophila, FTD, Glypican, Mushroom bodies, RNA-Seq, TDP-43, Wnt signaling

Medical Subject Headings

Animals; Humans; Amyotrophic Lateral Sclerosis (pathology); DNA-Binding Proteins (genetics, metabolism); Drosophila (metabolism); Frontotemporal Dementia (genetics, pathology); Motor Neurons (metabolism); Pick Disease of the Brain (pathology); RNA, Messenger; TDP-43 Proteinopathies (pathology)

Publication Date

10-20-2023

Publication Title

Acta neuropathologica communications

E-ISSN

2051-5960

Volume

11

Issue

1

First Page

168

PubMed ID

37864255

Digital Object Identifier (DOI)

10.1186/s40478-023-01656-0

Recommended Citation

Godfrey, R Keating; Alsop, Eric; Bjork, Reed T.; Chauhan, Brijesh S.; Ruvalcaba, Hillary C.; Antone, Jerry; Gittings, Lauren M.; Michael, Allison F.; Williams, Christi; Hala'ufia, Grace; Blythe, Alexander D.; Hall, Megan; Sattler, Rita; Van Keuren-Jensen, Kendall; and Zarnescu, Daniela C., "Modelling TDP-43 proteinopathy in Drosophila uncovers shared and neuron-specific targets across ALS and FTD relevant circuits" (2023). Translational Neuroscience. 2368.
https://scholar.barrowneuro.org/neurobiology/2368