TDP-1/TDP-43 potentiates human α-Synuclein (HASN) neurodegeneration in Caenorhabditis elegans

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1866

Article

Shen, Linjing¹  Wang, Changliang¹  Chen, Liang^2,3  Leung, Ka Lai¹  Lo, Esther¹  Lakso, Merja¹  Wong, Garry¹ 

[1] Univ Macau, Fac Hlth Sci, Ctr Reprod Dev & Aging, Ave Univ, Taipa 999078, Macau Sar, Peoples R China

[2] Shantou Univ, Coll Engn, Dept Comp Sci, Shantou 515063, Peoples R China

[3] Shantou Univ, Key Lab Intelligent Mfg Technol, Minist Educ, Shantou 515063, Peoples R China

关键词: alpha-Synuclein;    TDP-1/TDP-43;    tdp-43;    Parkinson's disease;    Lewy body dementia;    C. elegans;    Neurodegeneration;   

DOI  :  10.1016/j.bbadis.2020.165876

来源: Elsevier

【 摘 要 】

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 alpha-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.

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