Biology subjects

Nahidiazar, L.

Publications and source records attributed to Nahidiazar, L..

5 recordsLinked to original sources

bioRxiv2025

Microglial activation and alpha-synuclein oligomers drive the early inflammatory phase of Parkinson's disease

Parkinsons disease (PD) is characterised by insoluble -synuclein (Syn) aggregates in Lewy bodies (LBs) within the substantia nigra, with cortical pathology appearing as the disease progresses. Late-stage LB deposition, cellular stress, and neuronal loss obscure disease-driving events, we therefore performed multi-regional transcriptomic and aggregate profiling in early-midstage PD brains (Braak 3-4), where cortical regions are pathologically unaffected. We report neuroimmune activation as an early PD feature, characterised by the expansion of a high-SNCA-expressing microglial state. This robust immune signature occurs prior to LB formation, but is associated with oligomeric Syn within cortical microglia. In hiPSC-derived microglia, both endogenous Syn oligomerisation, and exogenous oligomer uptake, trigger transcriptional reprogramming, characterised by interferon-driven inflammation, antigen presentation, and mitochondrial suppression, closely mirroring the early PD brain. These findings describe mechanisms by which Syn oligomerisation potently initiates early neuroinflammation, highlighting a critical interplay between proteinopathy and immune activation at the earliest stages of disease.

neuroscience↗

bioRxiv2025

Visualizing homology search in living cells

Homologous recombination (HR) is a DNA repair process that requires a homologous sequence for the repair of DNA double-stranded breaks. The search for homology is the rate limiting step for HR, but the dynamics of homology search in vivo are currently poorly understood. This is largely due to a lack of tools to visualize homology search in action in living human cells. Here, we show that RAD51 and MND1, two proteins operating in homology search, become visible in long filamentous structures several hours after double-stranded break formation. Using GFP-MND1 we can visualize these filaments in living human cells and find that they are highly dynamic, explore the nuclear space, and can resolve over time. We show that the resolution of these filaments depends on RAD54L, known for its role in RAD51-driven homology search and strand-invasion. In addition, we find that loss of cohesin also inhibits the resolution of these filaments, in accordance with a role for cohesin in HR. Thus, our data suggest that these filaments are visible intermediates of an active DNA repair process, and that MND1-GFP can be used as a tool to study the dynamics of homology search in living human cells.

cell biology↗

bioRxiv2019

Modular actin nano-architecture enables podosome protrusion and mechanosensing

Basement membrane transmigration during embryonal development, tissue homeostasis and tumor invasion relies on invadosomes, a collective term for invadopodia and podosomes. An adequate structural framework for this process is still missing. Here, we reveal the modular actin nano-architecture that enables podosome protrusion and mechanosensing. The podosome protrusive core contains a central branched actin module encased by a linear actin module, each harboring specific actin interactors and actin isoforms. From the core, two actin modules radiate: ventral filaments bound by vinculin and connected to the plasma membrane and dorsal interpodosomal filaments crosslinked by myosin IIA. On stiff substrates, the actin modules mediate long-range substrate exploration, associated with degradative behavior. On compliant substrates, the vinculin-bound ventral actin filaments shorten, resulting in short-range connectivity and a focally protrusive, non-degradative state. Our findings redefine podosome nanoscale architecture and reveal a paradigm for how actin modularity drives invadosome mechanosensing in cells that breach tissue boundaries.

cell biology↗

bioRxiv2018

Mechanisms of integrin αVβ5 clustering in flat clathrin lattices

Summary statementThis article highlights several molecular mechanisms that result in the assembly of integrin V{beta}5-containing flat clathrin lattices in human keratinocytes.\n\nAbstractThe family of integrin transmembrane receptors is essential for the normal function of multicellular organisms by facilitating cell-extracellular matrix adhesion. The vitronectin-binding integrin V{beta}5 localizes to focal adhesions (FAs) as well as poorly characterized flat clathrin lattices (FCLs). Here we show that in human keratinocytes V{beta}5 is predominant found in FCLs and that formation of the V{beta}5-containing FCLs requires the presence of vitronectin as ligand, calcium, and the clathrin adaptor proteins ARH, Numb, and EPS15/EPS15L1. Integrin chimeras, containing the extracellular and transmembrane domains of {beta}5 and the cytoplasmic domains of {beta}1 or {beta}3, almost exclusively localize in FAs. Interestingly, lowering actomyosin-mediated contractility promotes integrin redistribution to FLCs in an integrin tail-dependent manner, while increasing cellular tension favors V{beta}5 clustering in FAs. Our findings strongly indicate that clustering of integrin V{beta}5 in FCLs is dictated by the {beta}5 subunit cytoplasmic domain, cellular tension, and recruitment of specific adaptor proteins to the {beta}5 subunit cytoplasmic domains.

cell biology↗

bioRxiv2018

CLIC4 is regulated by RhoA-mDia2 signaling through Profilin-1 binding to modulate filopodia length

CLIC4 is a cytosolic protein implicated in diverse actin-based processes, including integrin trafficking, cell adhesion and tubulogenesis. CLIC4 is rapidly recruited to the plasma membrane by G12/13-coupled receptor agonists and then partly co-localizes with {beta}1 integrins. Receptor-mediated CLIC4 translocation depends on actin polymerization, but the mechanism and functional significance of CLIC4 trafficking are unknown. Here we show that RhoA activation by either LPA or EGF is necessary and sufficient for CLIC4 translocation, with a regulatory role for the RhoA effector mDia2, an inducer of actin polymerization. We find that CLIC4 directly interacts with the G-actin-binding protein Profilin-1 via conserved residues that are required for CLIC4 trafficking and lie in a concave surface. Consistently, silencing of Profilin-1 impaired CLIC4 trafficking induced by either LPA or EGF. CLIC4 knockdown promoted the formation of long integrin-dependent filopodia, a phenotype rescued by wild-type CLIC4 but not by trafficking-incompetent CLIC4(C35A). Our results establish CLIC4 as a Profilin-1-binding protein and suggest that CLIC4 translocation provides a feedback mechanism to modulate mDia2/Profilin-1-driven cortical actin assembly and membrane protrusion.

cell biology↗