Biology subjects

Modak, A. S.

Publications and source records attributed to Modak, A. S..

3 recordsLinked to original sources

bioRxiv2026

Neuronal lipid composition regulates distinct states of full-length tau assembly, mechanics and membrane interactions

Aggregation of tau into fibrillar assemblies and neurofibrillary tangles is a defining feature of tauopathies. However, the role of the membrane-rich neuronal environment on the assembly and mechanics of full-length tau remains unclear. Here, we examined how neuronal lipid membranes affect the assembly and membrane interaction of full-length human tau (hTau40). Lipid composition redirected hTau40 assembly, with total brain extract and brain phosphatidylcholine membrane producing shorter, more flexible fibrils, whereas brain phosphatidylserine membrane favoured a more heterogeneous and relatively rigid fibrillar population. Tau-membrane interaction depended strongly on the assembly state of tau. At the same protein concentration, preformed oligomers accumulated on membranes much more rapidly than monomeric tau, indicating that oligomer formation increases membrane recruitment. However, strong membrane binding did not directly predict the extent of membrane perturbation. Pronounced changes in lipid organisation were observed when tau was undergoing continued higher-order assembly at the membrane. Thus, the ability of tau to bind a membrane and its ability to reorganise that membrane appear to be related, but distinct, features of tau-membrane interaction. In cells, internalised hTau40 formed stable, low-mobility assemblies associated with the endolysosomal compartment and changes in its physical properties. These assemblies could also be transferred between cells in a membrane-derived vesicle model. Together, our results show that local membrane composition shapes tau assembly and mechanics, while the state of tau assembly influences how it binds to and remodels membranes. Key words: Amyloid, Tauopathy, Tau protein (Tau), Lipid Vesicle, Membrane Biophysics

biophysics↗

bioRxiv2025

Membrane Interfacial Potential Governs Surface Condensation andFibrillation of α-Synuclein in Neurons

Biomolecular condensates formed via liquid-liquid phase separation (LLPS) are essential for cellular organization. -Synuclein, an amyloidogenic protein linked to Parkinsons Disease (PD), undergoes phase separation at high concentrations, but the influence of lipid membranes on this process remains unclear. Here, combining in vitro reconstitution, cell biology, and simulations, we show that membranous interfaces promote -Synuclein condensation at physiologically relevant sub-critical concentrations ([~]10 nM) without crowding agents. Notably, condensation occurs only on membranes with a specific stoichiometry of lipids, underscoring the role of interfacial potential. These condensates serve as nucleation sites for fibril formation, leading to membrane deformation and rupture. A lattice gas model reveals this behavior as a prewetting-like transition, where an attractive membrane induces local phase separation below the bulk saturation concentration. Indeed altering interfacial potential by lipid composition and membrane depolarization not only drastically changes -Synuclein puncta size and number but also triggers their release from neurons. These findings reveal the crucial role of lipid membrane interfaces in regulating -Synuclein condensation, aggregation and release, shedding light on a potential mechanism of their cell-to-cell propagation during neurodegeneration.

biophysics↗

bioRxiv2024

Protective role of Pten downregulation in Huntington's Disease models

Huntingtons disease (HD) is a dominantly inherited neurodegenerative disorder that stems from the expansion of CAG repeats within the coding region of the Huntingtin gene. Currently, there exists no effective therapeutic intervention that can prevent the progression of the disease. Our investigation aims to identify a novel genetic modifier with therapeutic potential. We employ transgenic flies containing Htt93Q and Htt138Q.mRFP constructs, which encode mutant pathogenic Huntingtin proteins featuring 93 and 138 polyglutamine (Q) repeats, respectively. The resultant mutant protein causes the loss of photoreceptor neurons in the eye and a progressive loss of neuronal tissues in the brain and motor neurons in Drosophila. Several findings have demonstrated the association of HD with growth factor signaling defects. Phosphatase and tensin homolog (Pten) have been implicated in the negative regulation of insulin signaling/receptor tyrosine signaling pathway which regulates the growth and survival of cells. In the present study, we downregulated Pten and found a significant improvement in morphological phenotypes in the eye, brain, and motor neurons. These findings were further correlated with the enhancement of the functional vision and climbing ability of the flies. We also noted the reduction in both poly(Q) aggregate levels and caspase activity which are involved in the apoptotic pathway. Moreover, we elucidated the protective role of Pten inhibition through the utilization of VO-OHpic (referred to as PTENi). In alignment with the genetic modulation of Pten, pharmaceutical inhibition of Pten improved the climbing ability of flies and reduced the poly(Q) aggregates and apoptosis levels. A similar reduction in poly(Q) aggregates was observed in the mouse neuronal inducible HD cell line model. Our study illustrates that Pten inhibition is a potential therapeutic approach for HD.

neuroscience↗