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TAR-DNA binding protein (TDP-43) is a multifunctional ribonucleoprotein, which is involved in transcription, splicing and mRNA stablilisation. TDP-43 is predominantly localised in the nucleus but shuttles between nucleus and the cytoplasm. In a pathological situation it is depleted from the nucleus and found mislocalised in the cytoplasm where it is abnormally cleaved, phosphorylated, ubiquitinated and aggregated. TDP-43 has been implicated in wide range of neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration-U (FTLD-U). The relative impact of the endogenous protein function, alteration and mutations on disease progression or pathology remains unclear. In this study I addressed many questions pertaining to TDP-43 biology with both random and strict comparable expression levels. This study focused on developing and characterising Drosophila models of TDP-43 proteinopathy. In addition, this study investigated the role of ALS/FTLD linked mutations and alterations on neural integrity utilising Drosophila as model system. A direct role of TDP-43 in neurodegeneration is highlighted by the fact that neuronal expression of human TDP-43 in Drosophila causes age- and dose-dependent locomotion deficits and early lethality. Further, targeted expression of TDP-43 to the developing fly eye results in a rough eye phenotype (REP). In this study TDP-43 RNA-binding was found to be absolutely required for toxicity. ALS/FTLD linked mutations and other reported pathological events like mislocalisation or truncation were relatively less toxic when compared to TDP-43 wild-type. Further I performed a large-scale toxicity modifier screen for TDP-43 induced toxicity using REP as readout. I identified novel modifiers of TDP-43-induced toxicity in this genetic screen. The most prominent candidates were RNA/DNA related genes, ubiquitin proteasome pathway related genes and neuron related genes. In addition, I found a novel protein interactor DBNDD2/CK1BP of TDP-43 in a yeast-2- hybrid screen. In the end, I present a very potent model of TDP-43 proteinopathy, which recapitulates a wide range of neuropathological, biochemical and functional features of human TDP-43 proteinopathy. Further working with this model I could uncover many endogenous functions and toxicity modifiers of TDP-43 induced toxicity. This study enhances our knowledge on TDP-43 biology and potentially widens future research strategies.