Novel C. elegans models of Lewy body disease reveal pathological protein interactions and widespread miRNA dysregulation

Li, Rongzhen1; Huang, Xiaobing1,5; Shen, Linjing1,2; Zhang, Tianjiao1,3; Liu, Ning1; Hou, Xiangqing1,4; Wong, Garry1

2024-12-01

10.1007/s00018-024-05383-0

CELLULAR AND MOLECULAR LIFE SCIENCES   影响因子和分区

1420-682X

1420-9071

Lewy body diseases (LBD) comprise a group of complex neurodegenerative conditions originating from accumulation of misfolded alpha-synuclein (alpha-syn) in the form of Lewy bodies. LBD pathologies are characterized by alpha-syn deposition in association with other proteins such as Amyloid beta (A beta), Tau, and TAR-DNA-binding protein. To investigate the complex interactions of these proteins, we constructed 2 novel transgenic overexpressing (OE) C. elegans strains (alpha-syn(A53T);Tau(pro-agg) (OE) and alpha-syn(A53T);A beta 1-42;Tau(pro-agg) (OE)) and compared them with previously established Parkinson's, Alzheimer's, and Lewy Body Dementia disease models. The LBD models presented here demonstrate impairments including uncoordinated movement, egg-laying deficits, altered serotonergic and cholinergic signaling, memory and posture deficits, as well as dopaminergic neuron damage and loss. Expression levels of total and prone to aggregation alpha-syn protein were increased in alpha-syn(A53T);A beta(1-42) but decreased in alpha-syn(A53T);Tau(pro-agg) animals when compared to alpha-syn(A53T) animals suggesting protein interactions. These alterations were also observed at the mRNA level suggesting a pre-transcriptional mechanism. miRNA-seq revealed that cel-miR-1018 was upregulated in LBD models alpha-syn(A53T), alpha-syn(A53T);A beta(1-42), and alpha-syn(A53T);Tau(pro-agg) compared with WT. cel-miR-58c was upregulated in alpha-syn(A53T);Tau(pro-agg) but downregulated in alpha-syn(A53T) and alpha-syn(A53T);A beta(1-42) compared with WT. cel-miR-41-3p and cel-miR-355-5p were significantly downregulated in 3 LBD models. Our results obtained in a model organism provide evidence of interactions between different pathological proteins and alterations in specific miRNAs that may further exacerbate or ameliorate LBD pathology.

Amyloid beta alpha-Synuclein Tau protein TAR-DNA-binding protein 43 Parkinson's disease

SCI

英语

其他

Research Services and Knowledge Transfer Office, University of Macau["P40 OD010440","MYRG2020-00213-FHS"]

Biochemistry & Molecular Biology ; Cell Biology

Biochemistry & Molecular Biology ; Cell Biology

WOS:001303646400003

SPRINGER BASEL AG

MOLECULAR BIOLOGY & GENETICS

Web of Science

1.Univ Macau, Fac Hlth Sci, Ctr Reprod Dev & Aging, Canc Ctr, E12-3005 Ave Univ, Macau 999078, Peoples R China
2.Southern Univ Sci & Technol, Sch Med, Dept Biochem, Shenzhen 518055, Peoples R China
3.Wuyi Univ, Sch Pharm & Food Engn, Jiangmen 529020, Peoples R China
4.Guangzhou Int Bio Isl, Guangzhou Natl Lab, Guangzhou 510005, Peoples R China
5.Shenzhen Technol Univ, Coll Pharm, Shenzhen 518118, Peoples R China

Li, Rongzhen,Huang, Xiaobing,Shen, Linjing,et al. Novel C. elegans models of Lewy body disease reveal pathological protein interactions and widespread miRNA dysregulation[J]. CELLULAR AND MOLECULAR LIFE SCIENCES,2024,81(1).

Li, Rongzhen.,Huang, Xiaobing.,Shen, Linjing.,Zhang, Tianjiao.,Liu, Ning.,...&Wong, Garry.(2024).Novel C. elegans models of Lewy body disease reveal pathological protein interactions and widespread miRNA dysregulation.CELLULAR AND MOLECULAR LIFE SCIENCES,81(1).

Li, Rongzhen,et al."Novel C. elegans models of Lewy body disease reveal pathological protein interactions and widespread miRNA dysregulation".CELLULAR AND MOLECULAR LIFE SCIENCES 81.1(2024).