Biology subjects

Fierli, F.

Publications and source records attributed to Fierli, F..

3 recordsLinked to original sources

bioRxiv2025

Alpha-Synuclein co-pathology in Alzheimer's Disease drives tau accumulation

The molecular basis for accelerated cognitive decline seen in Alzheimers Disease (AD) cases presenting with cortical alpha-Synuclein (-Syn) co-pathology is not well understood. We show that such co-pathology brains express higher levels of microtubule-associated protein tau and that increasing -Syn expression is sufficient to drive tau accumulation. Our results reveal a hitherto unknown link between the pathogenesis of AD and Parkinsons Disease whereby tau and -Syn synergistically drive dementia-related pathology.

neuroscience↗

bioRxiv2024

Exploring the relationship between GBA1 host genotype and gut microbiome in the GBA1L444P/WT mouse model: Implications for Parkinson disease pathogenesis

BackgroundHeterozygous variants in GBA1 are the commonest genetic risk factor for Parkinson disease (PD) but penetrance is incomplete. GBA1 dysfunction can cause gastrointestinal disturbances and microbiome changes in preclinical models. Mounting evidence suggests that the microbiota-gut-brain axis is potentially implicated in PD pathogenesis. Whether the gut microbiome composition is influenced by host GBA1 genetics in heterozygosis has never been explored. ObjectivesTo evaluate whether heterozygosity for the GBA1 pathogenic L444P variant can cause perturbations in gut microbiome composition. MethodsFaecal samples collected from GBA1L444P/WT and GBA1WT/WT mice at 3 and 6 months of age were analysed through shotgun metagenomic sequencing. ResultsNo differences in - and {beta}-diversity were detected between genotyped groups, at either time points. Overall, we found a little variation of the gut microbiome composition and functional potential between GBA1L444P/WT and GBA1WT/WT mice over time. ConclusionHost GBA1 genotype does not impact gut microbiome structure and composition in the presented GBA1L444P/WT mouse model. Studies investigating the effect of a second hit on gut physiology and microbiome composition could explain the partial penetrance of GBA1 variants in PD.

neuroscience↗

bioRxiv2023

Reduction of a-synuclein aggregates by PIKfyve inhibition via TFEB-mediated lysosomal biogenesis in a Parkinson disease model

Parkinson disease is a neurodegenerative disorder characterised by impairment of motor function, and is associated with a progressive accumulation of insoluble aggregates of misfolded alpha-synuclein. In the present study, we exploited the SH-SY5Y cell model overexpressing a pro-aggregation form of alpha-synuclein to investigate the efficacy of PIKfyve-mediated lysosomal biogenesis, through TFEB, as potential target for Parkinson therapy. To investigate this, we exploited high-content imaging along with enzymatic assays to follow the progression of lysosomal biogenesis, lysosomal function and alpha-synuclein accumulation. The cellular model exploited in this study recapitulated important elements of the biochemical phenotype observed in Parkinson patient-derived neurons, including synuclein aggregates and impaired glucocerebrosidase (GCase) function. PIKfyve inhibition by YM201636 resulted in a lysosomal-dependant reduction of alpha-synuclein aggregates as early as 24 hours post-treatment. The mechanism of action of YM201636 was shown to be TFEB-mediated, with an increase in TFEB in the nuclei which subsequently resulted in increased lysosomal markers LAMP1 and GCase. PIKfyve inhibtion efficacy was also tested in differentiated SH-SY5Y cells, exhibiting a neuron-like morphology. In these cells, YM201636 also significantly reduced alpha-synuclein aggregates and increased TFEB nuclear presence. These findings suggest that PIKfyve inhibition could be exploited as therapeutic target for Parkinson disease.

neuroscience↗