TAR DNA binding protein (TDP-43) is a DNA/RNA binding protein whose pathological role in amyotrophic lateral sclerosis (ALS) and frontal temporal lobe dementia (FTLD) via formation of protein aggregates is well established. In contrast, knowledge concerning its interactions with other neuropathological aggregating proteins is poorly understood. Human α-synuclein (HASN) elicits dopaminergic neuron degeneration via protein aggregation in Parkinson's disease. HASN protein aggregates are also found in TDP-43 lesions and colocalize in Lewy Body Dementia (LBD). To better understand the interactions of TDP-43 and HASN, we investigated the effects of genetic deletion of tdp-1, the Caenorhabditis elegans ortholog of human TDP-43, as well as overexpression of TDP-43, in transgenic models overexpressing HASN^WT and HASN^A53T. Tdp-1 deletion improved the posture, movement, and developmental delay observed in transgenic animals pan-neuronally overexpressing HASN^A53T, and attenuated the loss and impairment of dopaminergic neurons caused by HASN^A53T or HASN^WT overexpression. Tdp-1 deletion also led to a decrease in protein level, mRNA level and aggregate formation of HASN in living animals. RNA-seq studies suggested that tdp-1 supports expression of lysosomal genes and decreases expression of genes involved in heat shock. RNAi demonstrated that heat shock proteins can mediate HASN neuropathology. Co-overexpression of both human TDP-43 and HASN^WT resulted in locomotion deficits, shorter lifespan, and more severe dopaminergic neuron impairments compared to single transgenes. Our results suggest TDP-1/TDP-43 potentiates HASN mediated neurodegeneration in C. elegans. This study indicates a multifunctional role for TDP-1/TDP-43 in neurodegeneration involving HASN.

TAR DNA结合蛋白（TDP-43）是一种DNA / RNA结合蛋白，通过蛋白质聚集体的形成，其在肌萎缩性侧索硬化症（ALS）和额颞叶性痴呆（FTLD）中的病理作用已得到充分证实。相反，关于其与其他神经病理学聚集蛋白相互作用的知识知之甚少。人α-突触核蛋白（HASN）通过帕金森氏病中的蛋白质聚集引起多巴胺能神经元变性。HASN蛋白聚集体还存在于TDP-43病变中，并在路易体痴呆症（LBD）中共定位。为了更好地了解TDP-43与HASN的相互作用，我们研究了秀丽隐杆线虫tdp-1基因缺失的影响在过表达HASN ^WT和HASN ^A53T的转基因模型中，人类TDP-43的直系同源基因以及TDP-43的过表达。Tdp-1缺失改善了泛神经过表达HASN ^A53T的转基因动物中观察到的姿势，运动和发育延迟，并减轻了由HASN ^A53T或HASN ^WT过表达引起的多巴胺能神经元的丢失和损伤。Tdp-1缺失还导致动物体内蛋白质水平，mRNA水平和HASN聚集体形成的降低。RNA-seq研究表明tdp-1支持溶酶体基因的表达并减少涉及热休克的基因的表达。RNAi证明热激蛋白可以介导HASN神经病理学。与单个转基因相比，人TDP-43和HASN ^WT的共同过表达导致运动缺陷，寿命缩短和多巴胺能神经元损伤。我们的结果表明TDP-1 / TDP-43 potentiates介导不是招在神经变性Ç。线虫。这项研究表明TDP-1 / TDP-43在涉及HASN的神经变性中具有多功能作用。