Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 2 de 2
Filter
Add more filters










Database
Language
Publication year range
1.
Insects ; 14(2)2023 Feb 09.
Article in English | MEDLINE | ID: mdl-36835737

ABSTRACT

Parkinson's disease (PD) is a heterogeneous and complex neurodegenerative disorder and large-scale genetic studies have identified >130 genes associated with PD. Although genomic studies have been decisive for our understanding of the genetic contributions underlying PD, these associations remain as statistical associations. Lack of functional validation limits the biological interpretation; however, it is labour extensive, expensive, and time consuming. Therefore, the ideal biological system for functionally validating genetic findings must be simple. The study aim was to assess systematically evolutionary conserved PD-associated genes using Drosophila melanogaster. From a literature review, a total of 136 genes have found to be associated with PD in GWAS studies, of which 11 are strongly evolutionary conserved between Homo sapiens and D. melanogaster. By ubiquitous gene expression knockdown of the PD-genes in D. melanogaster, the flies' escape response was investigated by assessing their negative geotaxis response, a phenotype that has previously been used to investigate PD in D. melanogaster. Gene expression knockdown was successful in 9/11 lines, and phenotypic consequences were observed in 8/9 lines. The results provide evidence that genetically modifying expression levels of PD genes in D. melanogaster caused reduced climbing ability of the flies, potentially supporting their role in dysfunctional locomotion, a hallmark of PD.

2.
Commun Biol ; 4(1): 509, 2021 04 30.
Article in English | MEDLINE | ID: mdl-33931719

ABSTRACT

Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease characterized by death of motor neurons. The etiology and pathogenesis remains elusive despite decades of intensive research. Herein, we report that dysregulated metabolism plays a central role in the SOD1 G93A mouse model mimicking ALS. Specifically, we report that the activity of carnitine palmitoyl transferase 1 (CPT1) lipid metabolism is associated with disease progression. Downregulation of CPT1 activity by pharmacological and genetic methods results in amelioration of disease symptoms, inflammation, oxidative stress and mitochondrial function, whereas upregulation by high-fat diet or corticosterone results in a more aggressive disease progression. Finally, we show that downregulating CPT1 shifts the gut microbiota communities towards a protective phenotype in SOD1 G93A mice. These findings reveal that metabolism, and specifically CPT1 lipid metabolism plays a central role in the SOD1 G93A mouse model and shows that CPT1 might be a therapeutic target in ALS.


Subject(s)
Amyotrophic Lateral Sclerosis/drug therapy , Carnitine O-Palmitoyltransferase/antagonists & inhibitors , Disease Models, Animal , Epoxy Compounds/pharmacology , Gastrointestinal Microbiome , Mutation , Superoxide Dismutase-1/physiology , Amyotrophic Lateral Sclerosis/metabolism , Amyotrophic Lateral Sclerosis/pathology , Animals , Disease Progression , Down-Regulation , Enzyme Inhibitors/pharmacology , Female , Male , Mice , Mice, Inbred C57BL , Mice, Knockout
SELECTION OF CITATIONS
SEARCH DETAIL
...