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

Acta Neuropathologica Communications

Research

Brijesh S. Chauhan¹  Hillary C. Ruvalcaba²  Reed T. Bjork²  Christi Williams²  Allison F. Michael²  Grace Hala’ufia²  Alexander D. Blythe²  Daniela C. Zarnescu³  R. Keating Godfrey⁴  Rita Sattler⁵  Lauren M. Gittings⁵  Kendall Van Keuren-Jensen⁶  Megan Hall⁶  Eric Alsop⁶  Jerry Antone⁶ 

[1] Cellular and Molecular Physiology, Penn State College of Medicine, 500 University Drive Crescent Building C4605, 17033, Hershey, PA, USA;Department of Molecular and Cellular Biology, Life Sciences South, University of Arizona, 1007 E. Lowell St., 85721, Tucson, AZ, USA;Department of Molecular and Cellular Biology, Life Sciences South, University of Arizona, 1007 E. Lowell St., 85721, Tucson, AZ, USA;Cellular and Molecular Physiology, Penn State College of Medicine, 500 University Drive Crescent Building C4605, 17033, Hershey, PA, USA;Department of Molecular and Cellular Biology, Life Sciences South, University of Arizona, 1007 E. Lowell St., 85721, Tucson, AZ, USA;McGuire Center for Lepidoptera and Biodiversity, Florida Museum of Natural History, University of Florida, 3215 Hull Road, 32611, Gainesville, FL, USA;Department of Translational Neuroscience, Barrow Neurological Institute, 350 W Thomas Road, 85013, Phoenix, AZ, USA;Translational Genomics Research Institute, 445 N 5th St., 85004, Phoenix, AZ, USA;

关键词: ALS;    FTD;    TDP-43;    Drosophila;    Mushroom bodies;    RNA-Seq;    Glypican;    Wnt signaling;   

DOI  :  10.1186/s40478-023-01656-0

 received in 2023-08-03, accepted in 2023-09-19,  发布年份 2023

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY   
© BioMed Central Ltd., part of Springer Nature 2023

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