Biology subjects

Tasdemir-Yilmaz, O. E.

Publications and source records attributed to Tasdemir-Yilmaz, O. E..

3 recordsLinked to original sources

bioRxiv2024

Glial state changes and neuroinflammatory RIPK1 signaling are a key feature of ALS pathogenesis

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that causes motor neuron loss in the brain and spinal cord. Neuroinflammation driven by activated microglia and astrocytes is prominent in ALS, but an understanding of cell state dynamics and which pathways contribute to the disease remains unclear. Single nucleus RNA sequencing of ALS spinal cords demonstrated striking changes in glial cell states, including increased expression of inflammatory and glial activation markers. Many of these signals converged on RIPK1 and the necroptotic cell death pathway. Activation of the necroptosis pathway in ALS spinal cords was confirmed in a large bulk RNA sequencing dataset and at the protein level. Blocking RIPK1 kinase activity delayed symptom onset and motor impairment and modulated glial responses in SOD1G93A mice. We used a human iPSC-derived motor neuron, astrocyte, and microglia tri-culture system to identify potential biomarkers secreted upon RIPK1 activation, inhibited pharmacologically in vitro, and modulated in the CSF of people with ALS treated with a RIPK1 inhibitor. These data reveal ALS-enriched glial populations associated with inflammation and suggest a deleterious role for neuroinflammatory signaling in ALS pathogenesis.

neuroscience↗

bioRxiv2020

Diversity of developing peripheral glia revealed by single cell RNA sequencing

The peripheral nervous system responds to a wide variety of sensory stimuli, a process that requires great neuronal diversity. These diverse peripheral sensory neurons are closely associated with glial cells that originate from the neural crest (NC). However, the molecular nature and origins of diversity among peripheral glia is not understood. Here we used single cell RNA sequencing to profile and compare developing and mature glia from somatosensory lumbar dorsal root ganglia (DRG) and auditory spiral ganglia (SG). We found that the glial precursors (GPs) differ in their transcriptional profile and prevalence in these two systems. Despite their unique features, somatosensory and auditory GPs undergo convergent differentiation to generate myelinating and non-myelinating Schwann cells that are molecularly uniform. By contrast, although satellite glia surround the neuronal cell bodies in both ganglia, we found that those in the SG express multiple myelination-associated genes, while DRG satellite cells express components that suppress myelination. Lastly, we identified a set of glial signature genes that are also expressed by placode-derived supporting cells, providing new insights into commonalities among glia across the nervous system. This comprehensive survey of gene expression in peripheral glia constitutes a valuable resource for understanding how glia acquire specialized functions and how their roles differ across sensory modalities.

neuroscience↗

bioRxiv2020

Fast transport of RNA granules by direct interactions with KIF5A/KLC1 motors prevents axon degeneration

Complex neural circuitry requires stable connections formed by lengthy axons. To maintain these functional circuits, fast transport delivers RNAs to distal axons where they undergo local translation. However, the mechanism that enables long distance transport of non-membrane enclosed organelles such as RNA granules is not known. Here we demonstrate that a complex containing RNA and the RNA-binding protein (RBP) SFPQ interacts directly with a tetrameric kinesin containing the adaptor KLC1 and the motor KIF5A. We show that binding of SFPQ to KIF5A/KLC1 motor complex is required for axon survival and is impacted by KIF5A mutations that cause Charcot-Marie-Tooth (CMT) Disease. Moreover, therapeutic approaches that bypass the need for local translation of SFPQ-bound proteins prevent axon degeneration in CMT models. Collectively, these observations show that non-membrane enclosed organelles can move autonomously and that replacing axonally translated proteins provides a therapeutic approach to axonal degenerative disorders.

cell biology↗