TDP-43 knockdown impairs neurite outgrowth dependent on its target histone deacetylase 6

Molecular Neurodegeneration

Philipp J Kahle²  Stephanie S Weber¹  Christine Schurr¹  Fabienne C Fiesel¹ 

[1] Laboratory of Functional Neurogenetics, Department of Neurodegeneration, Hertie Institute for Clinical Brain Research, Otfried-Mueller-Str. 27, Tuebingen, 72076, Germany;German Center for Neurodegenerative Diseases, University of Tuebingen, Otfried-Mueller-Str. 27, Tuebingen, 72076, Germany

关键词: amyotrophic lateral sclerosis;    frontotemporal dementia;    SH-SY5Y neuroblastoma;    neurite outgrowth;    HDAC6;    RNAi;    TDP-43;   

Others  :  865623
DOI  :  10.1186/1750-1326-6-64

 received in 2010-10-12, accepted in 2011-08-30,  发布年份 2011

【 摘 要 】

Background

Trans-activation response element (TAR) DNA binding protein of 43kDa (TDP-43) is causally related to the neurodegenerative diseases frontotemporal dementia and amyotrophic lateral sclerosis being the hallmark protein in the disease-characteristic neuropathological lesions and via genetic linkage. Histone deacetylase 6 (HDAC6) is an established target of the RNA-binding protein TDP-43. HDAC6 is an unusual cytosolic deacetylase enzyme, central for a variety of pivotal cellular functions including aggregating protein turnover, microtubular dynamics and filopodia formation. All these functions are important in the context of neurodegenerative proteinopathies involving TDP-43. We have previously shown in a human embryonic kidney cell line that TDP-43 knockdown significantly impairs the removal of a toxic, aggregating polyQ ataxin-3 fusion protein in an HDAC6-dependent manner. Here we investigated the influence of TDP-43 and its target HDAC6 on neurite outgrowth.

Results

Human neuroblastoma SH-SY5Y cells with stably silenced TDP-43 showed a significant reduction of neurite outgrowth induced by retinoic acid and brain-derived neurotrophic factor. Re-transfection with TDP-43 as well as HDAC6 rescued retinoic acid-induced neurite outgrowth. In addition, we show that silencing of HDAC6 alone is sufficient to reduce neurite outgrowth of in vitro differentiated SH-SY5Y cells.

Conclusions

TDP-43 deficiency leads to impairment of neurite growth in an HDAC6-dependent manner, thereby contributing to neurodegenerative events in TDP-43 diseases.

【 授权许可】

   
2011 Fiesel et al; licensee BioMed Central Ltd.

【 图 表 】

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