Loss and gain of Drosophila TDP-43 impair synaptic efficacy and motor control leading to age-related neurodegeneration by loss-of-function phenotypes

Abstract

Cytoplasmic accumulation and nuclear clearance of TDP-43 characterize familial and sporadic forms of amyotrophic lateral sclerosis and frontotemporal lobar degeneration, suggesting that either loss or gain of TDP-43 function, or both, cause disease formation. Here we have systematically compared loss- and gain-of-function of Drosophila TDP-43, TAR DNA Binding Protein Homolog (TBPH), in synaptic function and morphology, motor control, and age-related neuronal survival. Both loss and gain of TBPH severely affect development and result in premature lethality. TBPH dysfunction caused impaired synaptic transmission at the larval neuromuscular junction (NMJ) and in the adult. Tissue-specific knockdown together with electrophysiological recordings at the larval NMJ also revealed that alterations of TBPH function predominantly affect pre-synaptic efficacy, suggesting that impaired pre-synaptic transmission is one of the earliest events in TDP-43-related pathogenesis. Prolonged loss and gain of TBPH in adults resulted in synaptic defects and age-related, progressive degeneration of neurons involved in motor control. Toxic gain of TBPH did not downregulate or mislocalize its own expression, indicating that a dominant-negative effect leads to progressive neurodegeneration also seen with mutational inactivation of TBPH. Together these data suggest that dysfunction of Drosophila TDP-43 triggers a cascade of events leading to loss-of-function phenotypes whereby impaired synaptic transmission results in defective motor behavior and progressive deconstruction of neuronal connections, ultimately causing age-related neurodegeneration.

Functional complementation in Drosophila to predict the pathogenicity of TARDBP variants: evidence for a loss-of-function mechanism

“…The Drosophila homolog is called TBPH and has, similar to its human counterpart, 2 RNA recognition motifs, a GRR and displays similar nucleic acid binding and messenger RNA splicing properties (Ayala et al, 2005). In recent studies, by our own and collaborating laboratories, both loss and gain of TBPH resulted in highly similar phenotypic and transcriptome alterations (Diaper et al, 2013b;Vanden Broeck et al, 2013). A consistent observation throughout these and other reports was that TBPH dysfunction, caused by either increased or decreased levels of TBPH, results in neuronal loss (Diaper et al, 2013a(Diaper et al, , 2013bFeiguin et al, 2009;Lin et al, 2011;Ritson et al, 2010;Vanden Broeck et al, 2013;Wang et al, 2011).…”

Drosophila as an In Vivo Model for Human Neurodegenerative Disease

“…Whereas the aforementioned studies highlighted toxic mechanisms upon expression of TDP-43, studies in the fly on the endogenous TDP-43 homolog, TBPH, indicate that normal TBPH function is critical for the development and maintenance of the nervous system. Flies lacking TBPH have motor defects and reduced lifespan-features markedly similar to humans with ALS (Feiguin et al 2009;Lin et al 2011;Diaper et al 2013). These data from the fly support the idea that disease-associated toxicity of TDP-43 could involve both loss-of-function and gain-of-function mechanisms (reduced nuclear function and accumulation in the cytoplasm, respectively).…”

The Role of TDP-43 in Alzheimer’s Disease

“…TDP-43 granules are bidirectionally transported to neurons in vitro and vivo and assist delivery of target mRNA to distal neuronal compartments; mutations of TDP-43 impair this axonal transport in progress of neurodegeneration [72]. Prolonged loss or gain of TAR DNA-binding protein homolog (TBPH) affects presynaptic efficacy, then resulting in impaired presynaptic transmission and progressive deconstruction of neuronal connections [73]. As such, the role of TDP-43 in neuronal function is worth exploring in the future.…”