{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,2,21]],"date-time":"2025-02-21T11:54:40Z","timestamp":1740138880584,"version":"3.37.3"},"reference-count":52,"publisher":"Society for Neuroscience","issue":"39","license":[{"start":{"date-parts":[[2018,3,27]],"date-time":"2018-03-27T00:00:00Z","timestamp":1522108800000},"content-version":"vor","delay-in-days":211,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-sa\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Neurosci."],"published-print":{"date-parts":[[2017,9,27]]},"abstract":"<jats:p>Defects in the RNA-binding protein, TDP-43, are known to cause a variety of neurodegenerative diseases, including amyotrophic lateral sclerosis and frontotemporal lobar dementia. A variety of experimental systems have shown that neurons are sensitive to TDP-43 expression levels, yet the specific functional defects resulting from TDP-43 dysregulation have not been well described. Using the<jats:italic>Drosophila<\/jats:italic>TDP-43 ortholog TBPH, we previously showed that TBPH-null animals display locomotion defects as third instar larvae. Furthermore, loss of TBPH caused a reduction in<jats:italic>cacophony<\/jats:italic>, a Type II voltage-gated calcium channel, expression and that genetically restoring<jats:italic>cacophony<\/jats:italic>in motor neurons in TBPH mutant animals was sufficient to rescue the locomotion defects. In the present study, we examined the relative contributions of neuromuscular junction physiology and the motor program to the locomotion defects and identified subsets of neurons that require<jats:italic>cacophony<\/jats:italic>expression to rescue the defects. At the neuromuscular junction, we showed mEPP amplitudes and frequency require TBPH.<jats:italic>Cacophony<\/jats:italic>expression in motor neurons rescued mEPP frequency but not mEPP amplitude. We also showed that TBPH mutants displayed reduced motor neuron bursting and coordination during crawling and restoring<jats:italic>cacophony<\/jats:italic>selectively in two pairs of cells located in the brain, the AVM001b\/2b neurons, also rescued the locomotion and motor defects, but not the defects in neuromuscular junction physiology. These results suggest that the behavioral defects associated with loss of TBPH throughout the nervous system can be associated with defects in a small number of genes in a limited number of central neurons, rather than peripheral defects.<\/jats:p><jats:p><jats:bold>SIGNIFICANCE STATEMENT<\/jats:bold>TDP-43 dysfunction is a common feature in neurodegenerative diseases, including amyotrophic lateral sclerosis, frontotemporal lobar dementia, and Alzheimer's disease. Loss- and gain-of-function models have shown that neurons are sensitive to TDP-43 expression levels, but the specific defects caused by TDP-43 loss of function have not been described in detail. A<jats:italic>Drosophila<\/jats:italic>loss-of-function model displays pronounced locomotion defects that can be reversed by restoring the expression levels of a voltage-gated calcium channel,<jats:italic>cacophony.<\/jats:italic>We show these defects can be rescued by expression of<jats:italic>cacophony<\/jats:italic>in motor neurons and by expression in two pairs of neurons in the brain. These data suggest that loss of TDP-43 can disrupt the central circuitry of the CNS, opening up identification of alternative therapeutic targets for TDP-43 proteinopathies.<\/jats:p>","DOI":"10.1523\/jneurosci.0554-17.2017","type":"journal-article","created":{"date-parts":[[2017,8,29]],"date-time":"2017-08-29T00:25:36Z","timestamp":1503966336000},"page":"9486-9497","source":"Crossref","is-referenced-by-count":8,"title":["Restoration of Motor Defects Caused by Loss of<i>Drosophila<\/i>TDP-43 by Expression of the Voltage-Gated Calcium Channel,<i>Cacophony<\/i>, in Central Neurons"],"prefix":"10.1523","volume":"37","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8575-1940","authenticated-orcid":false,"given":"Kayly M.","family":"Lembke","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6970-305X","authenticated-orcid":false,"given":"Charles","family":"Scudder","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1320-653X","authenticated-orcid":false,"given":"David B.","family":"Morton","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"393","published-online":{"date-parts":[[2017,8,28]]},"reference":[{"key":"2023041803270964000_37.39.9486.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2006.10.093"},{"key":"2023041803270964000_37.39.9486.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2005.02.038"},{"key":"2023041803270964000_37.39.9486.3","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.038950"},{"key":"2023041803270964000_37.39.9486.4","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1152\/jn.1998.79.1.361","article-title":"Coupling of efferent neuromodulatory neurons to rhythmical leg motor activity in the locust","volume":"79","author":"Baudoux","year":"1998","journal-title":"J Neurophysiol"},{"key":"2023041803270964000_37.39.9486.5","doi-asserted-by":"publisher","DOI":"10.1186\/1750-1326-8-23"},{"key":"2023041803270964000_37.39.9486.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2014.09.064"},{"key":"2023041803270964000_37.39.9486.7","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2013.11.019"},{"key":"2023041803270964000_37.39.9486.8","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.271.42.25735"},{"key":"2023041803270964000_37.39.9486.9","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2012.02.032"},{"key":"2023041803270964000_37.39.9486.10","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddt243"},{"key":"2023041803270964000_37.39.9486.11","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddt005"},{"key":"2023041803270964000_37.39.9486.12","unstructured":"Engel AG (2008) Synaptic electrophysiology of the Drosophila neuromuscular junction. 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