Human amyloid beta and α-synuclein co-expression in neurons impair behavior and recapitulate features for Lewy body dementia in Caenorhabditis elegans.
Biochim Biophys Acta Mol Basis Dis
; 1867(10): 166203, 2021 10 01.
Article
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| MEDLINE
| ID: mdl-34146705
Amyloid ß (Aß), a product of APP, and SNCA (α-synuclein (α-syn)) are two of the key proteins found in lesions associated with the age-related neurodegenerative disorders Alzheimer's disease (AD) and Parkinson's disease (PD), respectively. Previous clinical studies uncovered Aß and α-syn co-expression in the brains of patients, which lead to Lewy body dementia (LBD), a disease encompassing Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD). To explore the pathogenesis and define the relationship between Aß and α-syn for LBD, we established a C. elegans model which co-expresses human Aß and α-syn with alanine 53 to threonine mutant (α-syn(A53T)) in pan-neurons. Compared to α-syn(A53T) single transgenic animals, pan-neuronal Aß and α-syn(A53T) co-expression further enhanced the thrashing, egg laying, serotonin and cholinergic signaling deficits, and dopaminergic neuron damage in C. elegans. In addition, Aß increased α-syn expression in transgenic animals. Transcriptome analysis of both Aß;α-syn(A53T) strains and DLB patients showed common downregulation in lipid metabolism and lysosome function genes, suggesting that a decrease of lysosome function may reduce the clearance ability in DLB, and this may lead to the further pathogenic protein accumulation. These findings suggest that our model can recapitulate some features in LBD and provides a mechanism by which Aß may exacerbate α-syn pathogenesis.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Péptidos beta-Amiloides
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Caenorhabditis elegans
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Enfermedad por Cuerpos de Lewy
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Alfa-Sinucleína
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Neuronas
Tipo de estudio:
Prognostic_studies
Límite:
Aged
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Animals
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Humans
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Middle aged
Idioma:
En
Revista:
Biochim Biophys Acta Mol Basis Dis
Año:
2021
Tipo del documento:
Article
País de afiliación:
China
Pais de publicación:
Países Bajos