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