Biology subjects

Birol, M.

Publications and source records attributed to Birol, M..

6 recordsLinked to original sources

bioRxiv2026

Tau spreading coordinates intercellular lipid flux enhancing neuronal resilience to lipid toxicity

The presence of intrinsically disordered proteins (IDPs) in the extracellular environment of the brain suggests that protein disorder may serve functions beyond those confined to the intracellular space. Tau, a prototypical IDP linked to tauopathies, a class of neurodegenerative diseases, is continuously released and spreads between cells in the brain, yet the biological significance of this extracellular phase remains unresolved. Here, we show that spreading tau coordinates neutral lipid homeostasis by promoting neuronal lipid efflux and enhancing resilience to lipid toxicity. Integrating transcriptomics and lipidomics, we demonstrate that tau spreading reprograms lipid transport pathways and triggers redistribution of triacylglycerol pools, remodeling neutral lipid metabolism. Mechanistically, cellular uptake of spreading tau drives its accumulation within neutral lipid-rich compartments and promotes neuronal lipid efflux. The exported lipids are enriched in peroxidized species that are subsequently transferred to astrocytes, reducing neuronal lipid stress and revealing a pathway through which tau regulates lipid homeostasis. Our findings reframe spreading tau as a regulator of intercellular lipid flux and position protein disorder as an active mediator of cell-to-cell communication in coordinating tissue metabolism. Loss of this homeostatic function is likely to contribute to the early metabolic dysfunction associated with tauopathy.

neuroscience↗

bioRxiv2026

Spreading α-synuclein rewires organelle communication and impairs neuron-astrocyte mitochondrial quality control

Progressive intercellular spreading of -synuclein (S) is implicated in pathology initiation and propagation of synucleinopathies. However, how recipient neurons respond to incoming S and whether these responses contribute to disease-associated early metabolic events, remains unknown. Here, using extracellular monomeric S to model the earliest cellular response to spreading, we found that internalized S accumulates at tri-organelle contact sites linking mitochondria, endoplasmic reticulum, and endo/lysosomal compartments. At these interfaces, S stabilizes generally dynamic contacts and constrains their remodeling, thereby rewiring organelle communication. These effects require the acidic S C-terminus and are not recapitulated by intracellular S overexpression. Proteomic profiling of S-associated mitochondria identified a contact site-enriched but quality-control-deficient state. Functionally, spreading S impairs neuron-astrocyte mitochondrial quality control (MQC) by reducing neuronal mitochondria transfer to astrocytes, while enhancing mitochondrial import. Our findings establish organelle contact sites as critical target of spreading S, through which rewired organelle communication impairs MQC and neuron-astrocyte crosstalk.

neuroscience↗

bioRxiv2026

A bio-orthogonal and covalent 5 kDa small protein tag

Precise and minimally perturbative protein labelling remains a key challenge for studying biomolecular function in living systems. Here, a minimal way to specifically label proteins based on SNAP-tag and intein-mediated protein splicing reaction is introduced. Termed CLUSTER (for Chemical Label-Unfold-Splice Technology Enables Recombination), this chimeric platform supports efficient labelling across diverse targets in living cells by retaining a fluorescent, 5 kDa sized peptide on a fusion protein of interest after splicing. A bacterial screening workflow was developed to optimize the reaction efficiency and construct design. Quantitative characterization using fluorescence polarization provides mechanistic insight into labelling efficiency and dynamics, while molecular dynamics simulations elucidate its stability, grasping the intricate nature of protein behaviour upon covalent labelling. This bio-orthogonal labelling technology allows for a versatile and minimally invasive approach for protein labelling, providing a powerful tool to probe protein behavior in native cellular systems.

synthetic biology↗

bioRxiv2023

The C-terminus of alpha-Synuclein regulates its dynamic cellular internalization by Neurexin 1 beta

The aggregation of the disordered neuronal protein, -Synuclein (S), is the primary pathological feature of Parkinsons disease. Current hypotheses favor cell-to-cell spread of S species as underlying disease progression, driving interest in identifying the molecular and cellular species involved in cellular internalization of S. Prior work from our lab identified the chemically specific interaction between S and the pre-synaptic adhesion protein neurexin 1{beta} (N1{beta}) to be capable of driving cellular internalization of both monomer and aggregated forms of S. Here we explore the physical basis of N1{beta}-driven internalization of S. Specifically, we show that spontaneous internalization of S by SH-SY5Y and HEK293 cells expressing N1{beta} requires essentially all of the membrane-binding domain of S; S constructs truncated beyond residue 90 bind to N1{beta} in the plasma membrane of HEK cells, but are not internalized. Interestingly, prior to internalization, S and N1{beta} co-diffuse rapidly in the plasma membrane. S constructs that are not internalized show very slow mobility themselves, as well as slow N1{beta} diffusion. Finally, we find that truncated S is capable of blocking internalization of full-length S. Our results draw attention to the potential therapeutic value of blocking S-N1{beta} interactions.

biophysics↗

bioRxiv2018

α-Synuclein binds extracellular complex N-linked glycans

Cell-to-cell transmission of toxic forms of -Synuclein (S) is thought to underlie disease progression in Parkinsons disease. S in humans is constitutively N-terminally acetylated (Sacetyl), although the impact of this modification is relatively unexplored. Here we report that Sacetyl is more effective at inducing intracellular aggregation in primary neurons than unmodified S (Sun). We identify complex N-linked glycans as binding partners for Sacetyl, and demonstrate that cellular internalization of Sacetyl is reduced significantly upon cleavage of extracellular N-linked glycans, but not other carbohydrates. We verify binding of Sacetyl to N-linked glycans in vitro, using both isolated glycans and cell-derived proteoliposomes. Finally, we identify neurexin l{beta}, a neuronal glycoprotein, as capable of driving glycan-dependent uptake of Sacetyl. Importantly, our results are specific to Sacetyl as Sun does not demonstrate sensitivity for N-linked glycans. Our study identifies extracellular N-linked glycans, and neurexin l{beta} specifically, as key modulators of neuronal uptake of physiological Sacetyl drawing attention to the potential therapeutic value of Sacetyl-glycan interactions.

biophysics↗

bioRxiv2016

Structurally distinct oligomers of islet amyloid polypeptide mediate toxic and non-toxic membrane poration

Peptide mediated gain-of-toxic function is central to pathology in Alzheimers, Parkinsons and diabetes. In each system, self-assembly into oligomers is observed and can also result in poration of artificial membranes. Structural requirements for poration and the relationship of structure to cytotoxicity is unaddressed. Here, we focus on islet amyloid polypeptide (IAPP) mediated loss of insulin secreting cells in diabetics. Newly developed methods enable structure-function inquiry to focus on intracellular oligomers composed of hundreds of IAPP. The key insights are that porating oligomers are internally dynamic, grow in discrete steps and are not canonical amyloid. Moreover, two class of pores coexist; an IAPP-specific ligand establishes that only one is cytotoxic. Toxic rescue occurs by stabilizing non-toxic poration without displacing IAPP from mitochondria. These insights illuminate cytotoxic mechanism in diabetes and also provide a generalizable approach for inquiry applicable to other partially ordered protein assemblies.\n\nHighlightsO_LIThe peptide amyloid precursor, IAPP, forms two classes of membrane porating oligomers.\nC_LIO_LIThe two classes have a >100-fold difference in pore size with the large pore form correlated with mitochondrial depolarization and toxicity.\nC_LIO_LIA drug-like molecule distinguishes between the two oligomer classes and rescues toxicity by stabilizing non-toxic poration without displacing IAPP from the mitochondria.\nC_LIO_LIThe mechanism of pore-forming oligomer assembly includes stepwise coalescence of smaller, dynamic assemblies.\nC_LI

cell biology↗