Biology subjects

Bademosi, A.

Publications and source records attributed to Bademosi, A..

4 recordsLinked to original sources

bioRxiv2023

Rescuing early Parkinson-induced hyposmia prevents dopaminergic system failure

The classical diagnosis of Parkinsonism is based on motor symptoms that are the consequence of nigrostriatal pathway dysfunction and reduced dopaminergic output. However, a decade prior to the emergence of motor issues, patients frequently experience non-motor symptoms, such as a reduced sense of smell (hyposmia). The cellular and molecular bases for these early defects remain enigmatic. To explore this, we developed a new collection of five fruit fly models of familial Parkinsonism and conducted single-cell RNA sequencing on young brains of these models. Interestingly, cholinergic projection neurons are the most vulnerable cells and genes associated with presynaptic function are the most deregulated. Additional single nucleus sequencing of three specific brain regions of Parkinsons disease patients confirms these findings. Indeed, the disturbances lead to early synaptic dysfunction, notably affecting cholinergic olfactory projection neurons crucial for olfactory function in flies. Correcting these defects specifically in olfactory cholinergic interneurons in flies or inducing cholinergic signaling in Parkinson mutant human induced dopaminergic neurons in vitro using nicotine, both rescue age-dependent dopaminergic neuron decline. Hence, our research uncovers that one of the earliest indicators of disease in 5 different models of familial Parkinsonism is synaptic dysfunction in higher-order cholinergic projection neurons and this contributes to the development of hyposmia. Furthermore, the shared pathways of synaptic failure in these cholinergic neurons ultimately contribute to dopaminergic dysfunction later in life.

neuroscience↗

bioRxiv2023

Synapse-specific trapping of Syntaxin1a into nanoclusters by the general anesthetic isoflurane

General anesthetics disrupt brain network dynamics through multiple pathways, predominately through post-synaptic potentiation of GABAAR and pre-synaptic inhibition of neuroexocytosis. Common clinical general anesthetic drugs, such as propofol and isoflurane, have been shown to interact and interfere with a core component of the exocytic release machinery, Syntaxin1A, to cause impaired neurotransmitter release. Recent in vitro studies however suggest that these drugs to not affect all synapse subtypes equally. We investigated the role of Syntaxin1A in multiple neurotransmitter systems under isoflurane general anesthesia in the adult Drosophila brain using live-cell super resolution microscopy and optogenetic readouts of exocytosis. We found that effects of isoflurane anesthesia were neuron specific and only impaired Syntaxin1A activity in excitatory neurons at cholinergic synapses, but not inhibitory GABAergic or glutamatergic neurons. These results indicate that general anesthetics could work by producing successive bouts of inhibition across the brain, by reducing neuroexocytosis from excitatory neurons specifically as well as silencing arousal systems through GABAAR potentiation.

neuroscience↗

bioRxiv2022

RNA-deficient TDP-43 causes loss of free nuclear TDP-43 by sequestration

Dysfunction and aggregation of the RNA-binding protein, TDP-43, is the unifying hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Mechanisms and relative contributions of concurrent TDP-43 nuclear depletion, cytoplasmic accumulation, and post-translational modification to neurodegeneration remain unresolved. We employed CRISPR/Cas9-mediated fluorescent tagging to investigate how disease-associated stressors and pathological TDP-43 alter abundance, localisation, self-assembly, aggregation, solubility, and mobility dynamics of endogenous TDP-43 over time. Oxidative stress stimulated TDP-43 liquid-liquid phase separation into droplets or spherical shell-like anisosomes, which were not formed by over-expressed wild-type TDP-43. Further, nuclear RNA-binding-ablated or acetylation-mimicking TDP-43 rapidly formed anisosomes and inclusions that readily sequestered and depleted free normal nuclear TDP-43. The majority of total endogenous TDP-43 was sequestered into anisosomes, but retained high protein mobility and solubility. However, cytoplasmic RNA-deficient TDP-43 formed large phosphorylated inclusions that occasionally sequestered endogenous TDP-43, rendering it insoluble and immobile, indicating irreversible pathological transition. These findings suggest that post-translational modification and RNA-binding deficiency exacerbate TDP-43 aggregation and dysfunction by driving sequestration, mislocalisation, and depletion of normal nuclear TDP-43 in ALS and FTD.

neuroscience↗

bioRxiv2022

Fear extinction is regulated by long noncoding RNA activity at the synapse

Long noncoding RNAs (lncRNAs) represent a multidimensional class of regulatory molecules involved in many aspects of brain function. Emerging evidence indicates that lncRNAs are expressed at the synapse; however, a direct role for their activity in this subcellular compartment in memory formation has yet to be demonstrated. Using lncRNA capture-seq on synaptosomes, we identified a significant number of lncRNAs that accumulate at synapses within the infralimbic prefrontal cortex of adult male C57/Bl6 mice. Among these is a splice variant related to the stress-associated lncRNA, Gas5. RNA immunoprecipitation followed by mass spectrometry and single molecule imaging revealed that this Gas5 isoform, in association with the RNA binding proteins G3bp2 and Caprin1, regulates the activity-dependent trafficking and clustering of RNA granules in dendrites. In addition, we found that cell-type-specific, state-dependent, and synapse-specific knockdown of the Gas5 variant led to impaired fear extinction memory. These findings identify a new mechanism of fear extinction that involves the dynamic interaction between local lncRNA activity and the coordination of RNA condensates in the synaptic compartment.

neuroscience↗