Dataset Information

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

ABSTRACT: Lewy body diseases (LBD) comprise a group of complex neurodegenerative conditions originating from accumulation of misfolded alpha-synuclein (α-syn) in the form of Lewy bodies. LBD pathologies are characterized by α-syn deposition in association with other proteins such as Amyloid β (Aβ), Tau, and TAR-DNA-binding protein. To investigate the complex interactions of these proteins, we constructed 2 novel transgenic overexpressing (OE) C. elegans strains (α-syn_A53T;Tau_pro-agg (OE) and α-syn_A53T;Aβ1-42;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 α-syn protein were increased in α-syn_A53T;Aβ_1-42 but decreased in α-syn_A53T;Tau_pro-agg animals when compared to α-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 α-syn_A53T, α-syn_A53T;Aβ_1-42, and α-syn_A53T;Tau_pro-agg compared with WT. cel-miR-58c was upregulated in α-syn_A53T;Tau_pro-agg but downregulated in α-syn_A53T and α-syn_A53T;Aβ_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.

SUBMITTER: Li R

PROVIDER: S-EPMC11364739 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Li Rongzhen R Huang Xiaobing X Shen Linjing L Zhang Tianjiao T Liu Ning N Hou Xiangqing X Wong Garry G

Cellular and molecular life sciences : CMLS 20240830 1

Lewy body diseases (LBD) comprise a group of complex neurodegenerative conditions originating from accumulation of misfolded alpha-synuclein (α-syn) in the form of Lewy bodies. LBD pathologies are characterized by α-syn deposition in association with other proteins such as Amyloid β (Aβ), Tau, and TAR-DNA-binding protein. To investigate the complex interactions of these proteins, we constructed 2 novel transgenic overexpressing (OE) C. elegans strains (α-syn<sub>A53T</sub>;Tau<sub>pro-agg</sub> ...[more]

PMID: 39212733

Similar Datasets

Project description:DICER1 is a highly conserved RNase III endoribonuclease essential for the biogenesis of single-stranded mature microRNAs (miRNAs) from stem-loop precursor miRNAs. Somatic mutations in the RNase IIIb domain of DICER1 impair its ability to generate mature 5p miRNAs and are believed to drive tumorigenesis in DICER1 syndrome-associated and sporadic thyroid tumors. However, the DICER1-driven specific changes in miRNAs and resulting changes in gene expression are poorly understood in thyroid tissue. In this study, we profiled the miRNA (n=2,083) and mRNA (n=2,559) transcriptomes of 20 non-neoplastic, 8 adenomatous and 60 pediatric thyroid cancers (13 follicular thyroid cancers [FTC] and 47 papillary thyroid cancers [PTC]) of which 8 had DICER1 RNase IIIb mutations. All DICER1-mutant differentiated thyroid cancers (DTC) were follicular patterned (six follicular variant PTC and two FTC), none had lymph node metastasis. We demonstrate that DICER1 pathogenic somatic mutations were associated with a global reduction of 5p-derived miRNAs, including those particularly abundant in the non-neoplastic thyroid tissue such as let-7 and mir-30 families, known for their tumor suppressor function. There was also an unexpected increase of 3p miRNAs, possibly associated with DICER1 mRNA expression increase in tumors harboring RNase IIIb mutations. These abnormally expressed 3p miRNAs, which are otherwise low or absent in DICER1-wt DTC and non-neoplastic thyroid tissues, make up exceptional markers for malignant thyroid tumors harboring DICER1 RNase IIIb mutations. The extensive disarray in the miRNA transcriptome results in gene expression changes, which were indicative of positive regulation of cell-cycle. Moreover, differentially expressed genes point to increased MAPK signaling output and loss of thyroid differentiation comparable to the RAS-like subgroup of PTC (as coined by The Cancer Genome Atlas), which is reflective of the more indolent clinical behavior of these tumors.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets