Biology subjects

Brasseur, L.

Publications and source records attributed to Brasseur, L..

3 recordsLinked to original sources

bioRxiv2024

Network analysis of α-synuclein pathology progression reveals p21-activated kinases as regulators of vulnerability

-Synuclein misfolding and progressive accumulation drive a pathogenic process in Parkinson's disease, yet many brain regions develop more or less pathology than would be predicted by connectivity alone, indicating that intrinsic biological factors influence regional vulnerability. Here, we combined whole brain mapping of -synuclein pathology in wildtype mice 3 days to 9 months after seeding with network diffusion modeling based on anatomical connectivity to derive quantitative measures of regional vulnerability. To identify molecular drivers of this vulnerability, we generated a brain-wide sPAtial Neuron Gene Expression Atlas (PANGEA) and compared regional transcriptional profiles with model-derived vulnerability scores. Vulnerable regions were enriched for specific cellular programs. Specific kinases were also enriched in vulnerable regions, leading to the identification of group II p21-activated kinases (PAKs) as candidate regulators of -synucleinopathy. Pharmacological inhibition of group II PAKs reduced -synuclein aggregation and protected against neuron loss in primary neurons, remained effective when administered after pathology initiation, and suppressed pathology in vivo. Consistent with these findings, genetic depletion of PAK5/6 also suppressed -synuclein aggregation. Together, these results establish a framework linking network-level measures to cellular mechanisms of selective vulnerability and nominate group II PAKs as promising disease-modifying therapeutic targets for Parkinson's disease.

neuroscience↗

bioRxiv2023

Spatial transcriptomics reveals molecular dysfunction associated with Lewy pathology

Lewy pathology composed of -synuclein is the key pathological hallmark of Parkinsons disease (PD), found both in dopaminergic neurons that control motor function, and throughout cortical regions that control cognitive function. Recent work has investigated which dopaminergic neurons are most susceptible to death, but little is known about which neurons are vulnerable to developing Lewy pathology and what molecular changes an aggregate induces. In the current study, we use spatial transcriptomics to selectively capture whole transcriptome signatures from cortical neurons with Lewy pathology compared to those without pathology in the same brains. We find, both in PD and in a mouse model of PD, that there are specific classes of excitatory neurons that are vulnerable to developing Lewy pathology in the cortex. Further, we identify conserved gene expression changes in aggregate-bearing neurons that we designate the Lewy-associated molecular dysfunction from aggregates (LAMDA) signature. This gene signature indicates that neurons with aggregates downregulate synaptic, mitochondrial, ubiquitin-proteasome, endo-lysosomal, and cytoskeletal genes and upregulate DNA repair and complement/cytokine genes. However, beyond DNA repair gene upregulation, we find that neurons also activate apoptotic pathways, suggesting that if DNA repair fails, neurons undergo programmed cell death. Our results identify neurons vulnerable to Lewy pathology in the PD cortex and identify a conserved signature of molecular dysfunction in both mice and humans.

neuroscience↗

bioRxiv2021

C9orf72-derived poly-GA DPRs undergo endocytic uptake in iNPC-derived astrocytes and spread to motor neurons

Dipeptide repeat proteins (DPRs) are aggregation-prone polypeptides encoded by the pathogenic G4C2 repeat expansion in the C9orf72 gene, the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). In this study, we focus on the role of poly-GA DPRs in disease spread. We demonstrate that recombinant poly-GA oligomers can directly convert into solid-like aggregates and form characteristic &[beta]-sheet fibrils in vitro. To dissect the process of cell-to-cell DPR transmission, we closely follow the fate of poly-GA DPRs in either their oligomeric or fibrillized form after administration in the cell culture medium. We observe that poly-GA DPRs are taken up via dynamin-dependent and - independent endocytosis, eventually converging at the lysosomal compartment and leading to axonal swellings in neurons. We then use a co-culture system to demonstrate astrocyte-to- motor neuron DPR propagation, showing that astrocytes may internalise and release aberrant peptides in disease pathogenesis. Overall, our results shed light on the mechanisms of poly- GA cellular uptake and cell-to-cell propagation, suggesting lysosomal impairment as a possible feature underlying the cellular pathogenicity of these DPR species.

neuroscience↗