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Molecular signatures of altered energy metabolism and circadian rhythm perturbations in a model of synucleinopathy

ABSTRACT: A pathological role of alpha-synuclein (AS) aggregation in the nervous system is a recognized feature in Parkinson disease (PD) and related neurodegenerative conditions termed synucleinopathies. In order to characterize the cellular response in CNS to incipient and advanced AS aggregation, we applied spatial transcriptomics on brain sections derived from a mouse model at prodromal and symptomatic stages of pathology. Our spatially-resolved data point to unique perturbations in brain energy metabolism during the progression of AS pathology, such that there is an initial phase of hypermetabolism in disease-affected regions, which is followed by a profound decline leading to the symptomatic phase. This latter stage was also associated with drastic reduction in mRNA translation machinery, neuroinflammation and aberrant expression of molecular drivers controlling circadian rhythms. Collectively, these data offer novel opportunities in knowledge translation for mechanism-based drug discovery and potentially inform on biological markers reflecting disease progression in PD and related diseases.

ORGANISM(S): Mus musculus

PROVIDER: GSE274605 | GEO | 2026/01/13

REPOSITORIES: GEO

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Project description:Parkinsonâs disease (PD) and Dementia with Lewy bodies (DLB) are the two most common examples of synucleinopathies, i.e. human disorders that display intracellular deposition of the Alpha-synuclein (aSYN) protein. The two forms of aSYN deposits, intracellular Lewy bodies and Lewy neurites, are in the PD brain primarily found in the substantia nigra whereas in DLB brains they are diffusely spread in cortical and limbic areas. We are currently analyzing the protective effects on aSYN pathology by the molecular chaperone hsp70 in mice overexpressing wildtype human aSYN. Moreover, transgenic mice overexpressing hsp70 have been cross-bred with the aSYN mouse line. Intriguingly, the aSYN / hsp70 double transgenics display a pronounced reduction in biochemically assessed aSYN aggregation. Gene expression of these mice will not only provide insight into the disease mechanisms of aSYN pathology but its prevention by the overexpression of hsp70, leading to new potential avenues of treatment. Project 1: To investigate and compare alterations in gene expression profiles of brains from wild-type mice and mice overexpressing wildtype human aSYN, human hsp70 and aSYN / hsp70, respectively. The comparison of the expression profiles of the groups of mice: aSYN, Hsp70, aSYN/ Hsp70 and non-transgenic littermates will help to identify the genes that are involved in the mediation of aggregation toxicity of aSYN expression as well as the genes that may mediate an attenuation of aSYN pathology in hsp70-coexpressors. Project 1: Selection of animals Mice of 4 month old (n=6) of age of each background (aSYN, Hsp70, aSYN/ Hsp70 and non-transgenic littermates) will be used for RNA-extraction for a total of 24 mice. Preparation of samples For the proposed experiments, we will use the recommended procedures, as outlined by the consortium, for extracting and purifying RNA from whole brain homogenate. Briefly, RNA will be extracted by the trizol method and purified by using the RNeasy MinElute Cleanup (QIAGEN Inc., USA). RNA labeling and hybridization procedures will be carried out by the microarray consortium. SPECIAL NOTE: The samples will be sent upon availability. Gene Expression Microarray Analysis Six mice will be included in each group per timepoint to generate statistically testable data and limit the possible confound of individual mouse gene expression variations. The genome expression will be evaluated through the use of the GeneChipÂ® Mouse Genome 430 2.0 Array (Affymetrix) for each individual mouse constituting a total of 24 arrays for the proposed study. Gene expression data interpretation will be assisted by the Microarray Consortium Center bioinformatics core.

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Molecular signatures of altered energy metabolism and circadian rhythm perturbations in a model of synucleinopathy

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