Biology subjects

Michel, P. P.

Publications and source records attributed to Michel, P. P..

3 recordsLinked to original sources

bioRxiv2023

Parkinson's disease-derived alpha-Synuclein assemblies combined with TNFalpha and Prostaglandin E2 induces a specific chronic-type inflammatory phenotype in microglial cells

Parkinsons disease (PD) is a common age-related neurodegenerative disorder characterized by the aggregation of -synuclein (SYN) building up intraneuronal inclusions termed Lewy pathology. Mounting evidence suggests that neuron-released SYN aggregates could be central to microglial activation, which in turn mounts and orchestrates neuroinflammatory processes potentially harmful to neurons. Therefore, understanding the mechanisms that drive microglial cell activation, polarization and function in PD might have important therapeutic implications. Here, using primary microglia, we investigated the inflammatory potential of pure SYN fibrils derived from PD patients. We further explored and characterized microglial cell responses to a chronic-type inflammatory stimulation combining PD patient-derived SYN fibrils (FPD), Tumor necrosis factor- (TNF) and prostaglandin E2 (PGE2) (TPFPD). We showed that FPD hold stronger inflammatory potency than pure SYN fibrils generated de novo. When combined with TNF and PGE2, FPD polarizes microglia toward a particular functional phenotype departing from FPD-treated cells and featuring lower inflammatory cytokine and higher glutamate release. Whereas metabolomic studies showed that TPFPD-exposed microglia were closely related to classically activated M1 proinflammatory cells, notably with similar tricarboxylic acid cycle disruption, transcriptomic analysis revealed that TPFPD-activated microglia assume a unique molecular signature highlighting upregulation of genes involved in glutathione and iron metabolisms. In particular, TPFPD-specific upregulation of Slc7a11 (which encodes the cystine-glutamate antiporter xCT) was consistent with the increased glutamate response and cytotoxic activity of these cells toward midbrain dopaminergic neurons in vitro. Together, these data further extend the structure-pathological relationship of SYN fibrillar polymorphs to their innate immune properties and demonstrate that PD-derived SYN fibrils, TNF and PGE2 act in concert to drive microglial cell activation toward a specific and highly neurotoxic chronic-type inflammatory phenotype characterized by robust glutamate release and iron retention.

neuroscience↗

bioRxiv2020

Doxycycline interferes with tau amyloid aggregation abolishing its associated neuronal toxicity

Tauopathies are neurodegenerative disorders with increasing incidence and still without cure. The extensive time required for development and approval of novel therapeutics highlights the need for testing and repurposing known safe molecules. Since doxycycline impacts -synuclein aggregation and toxicity, herein we tested its effect on tau. We found that doxycycline reduces amyloid aggregation of the different isoforms of tau protein in a dose-dependent manner, remodeling the resultant species. Furthermore, doxycycline interacts with tau microtubule-binding domain preventing its aggregation. In a cell free system doxycycline also prevents tau seeding and in cell culture reduces toxicity of tau aggregates. Overall, our results expand the spectrum of action of doxycycline against aggregation-prone proteins, opening novel perspectives for its repurposing as a disease-modifying drug for tauopathies.

biophysics↗

bioRxiv2020

Doxycycline inhibits α-synuclein-associated pathologies in vitro and in vivo

Parkinsons disease (PD) and dementia with Lewy bodies (DLB) are neurodegenerative disorders characterized by the misfolding and aggregation of alpha-synuclein (aSyn). Doxycycline, a tetracyclic antibiotic shows neuroprotective effects, initially proposed to be due to its anti-inflammatory properties. More recently, an additional mechanism by which doxycycline may exert its neuroprotective effects has been proposed as it has been shown that it inhibits amyloid aggregation. Here, we studied the effects of doxycycline on aSyn aggregation in vivo, in vitro and in a cell free system using real-time quaking induced conversion (RT-QuiC). Our results show that doxycycline decreases the number and size of aSyn aggregates in cells. In addition, doxycycline inhibits the aggregation and seeding of recombinant aSyn, and attenuates the production of mitochondrial-derived reactive oxygen species. Finally, we found doxycycline induces a cellular redistribution of the aggregates in an animal model of PD that is associated with a recovery of dopaminergic function. In summary, we provide strong evidence that doxycycline treatment may be an effective strategy against synucleinopathies.

molecular biology↗