Biology subjects

Maday, S.

Publications and source records attributed to Maday, S..

6 recordsLinked to original sources

bioRxiv2026

TRPML1 positions lysosomes and regulates actin-membrane linkers in astrocyte processes

Lysosomes are critical for neuronal physiology and synaptic function, but their organization and roles within astrocytes, an integral component of the tripartite synapse, remain unknown. Here, we use a neuron-astrocyte coculture system that promotes stellate astrocyte morphology to investigate the trafficking of late endosomes and lysosomes (LELs) in astrocytes. As astrocyte branches mature, degradative activity becomes concentrated in the soma and LELs in branches undergo bidirectional motility that becomes progressively attenuated. We establish that the lysosomal cation channel TRPML1 drives LEL immobilization. TRPML1-mediated arrest involves myosin-Va tethering to the actin cytoskeleton, which may position LELs near peripheral astrocyte processes (PAPs), fine actin-enriched protrusions that can contact synapses. Strikingly, TRPML1 activity modulates the phosphorylation of ezrin, radixin, and moesin, actin-membrane linkers enriched in PAPs. These effects are rapid and transient, suggesting a role for lysosomal TRPML1 in regulating PAP membrane dynamics. Thus, TRPML1 positions LELs proximal to PAPs which may influence PAP structural plasticity and astrocyte-synapse contacts.

neuroscience↗

bioRxiv2025

Differential regulation of p62-ubiquitin conjugates in neurons versus astrocytes during cellular stress

Sequestosome 1/p62 (hereafter referred to as p62) is a multifunctional protein that orchestrates various cellular stress response pathways including autophagy, proteasome-mediated degradation, antioxidant defense, nutrient sensing, and inflammatory signaling. Mutations in distinct functional domains of p62 are linked with the neurodegenerative disease amyotrophic lateral sclerosis (ALS), underscoring its importance in neural cells. Neurons and astrocytes perform distinct roles in brain physiology and thus encounter a unique landscape of cellular stress. However, how p62 is regulated in these cell types in response to various stress modalities remains largely unexplored. Several functions for p62 depend on engagement with ubiquitinated substrates. Thus, we investigated how the regulation of p62-ubiquitin conjugates differs between neurons and astrocytes exposed to two stress modalities: lysosomal membrane damage and metabolic stress. Lysosomal damage triggered ubiquitin-dependent assembly of p62 puncta in both neurons and astrocytes. In contrast, nutrient deprivation elicited different responses between neurons and astrocytes. Neurons formed p62-ubiquitin structures more prominently and displayed a greater dependence on ubiquitin for p62 clustering. Together, these findings reveal cell-type-specific and stress-specific regulation of p62-ubiquitin conjugates, indicating that neurons and astrocytes can deploy distinct quality control strategies.

neuroscience↗

bioRxiv2025

Astrocytes mobilize a broader repertoire of lysosomal repair mechanisms than neurons

Lysosomal damage impairs proteostasis and contributes to neurodegenerative diseases, yet cell-type-specific differences in lysosomal repair remain unclear. Using a neuron-astrocyte coculture system, we compared responses to lysosomal injury induced by a lysosomotropic methyl ester. Both neurons and astrocytes showed lysosomal damage, marked by galectin-3 recruitment to lumenal lysosomal {beta}-galactosides, elevated lysosomal pH, and engagement of lysophagy receptors TAX1BP1 and p62. However, astrocytes showed a preferential recruitment of ESCRT repair machinery to damaged lysosomes. Additionally, the lysosomal membrane reformation pathway regulated by the RAB7-GAP, TBC1D15, was more robustly activated in astrocytes. By contrast, the PITT pathway, mediating lipid transfer between the ER and damaged lysosomes, was engaged in both cell types. Our data reveal a divergence in how neurons and astrocytes mobilize repair pathways to manage lysosomal damage. These data may reflect differences in lysosomal resilience between astrocytes and neurons and inform therapeutic strategies to correct lysosomal dysfunction in neurodegenerative diseases.

neuroscience↗

bioRxiv2025

An experimental approach to understanding plastic leachate impacts on marine microorganisms

Plastics in the worlds oceans are exposed to diverse environmental stressors that fragment them, accelerating the leaching of associated additives. The impact of potentially toxic plastic degradation products and additives on marine microorganisms remains poorly understood. We assessed the impact of plastic leachate on marine microbial communities in vitro by exposure to one of four plastic leachates (from linear low-density polyethylene [LLPDE], polyamide-6 [or polycaprolactam; PA6], polyethylene terephthalate [PET] and polylactic acid [PLA]), prepared by immersing plastics in artificial seawater salts broth for three months at 80 {degrees}C. Microbial communities were then exposed to different leachates, noting that lower concentrations of plastic additives leached from the more inert plastic types (LLDPE and PET), as determined by GC-MS. PLA-leachate exposed communities differed significantly in composition from other plastic-leachate-exposed communities (PERMANOVA, P=0.001) as assessed by 16S rRNA gene and ITS region amplicon sequencing. Communities exposed to PLA-leachate contained a higher proportion of Proteobacteria, specifically Halomonas spp., previously reported to degrade LDPE and common plasticisers. Greater relative abundances of Psathyrellaceae fungi also distinguished these communities from those exposed to other plastic leachates. However, despite significant differences in the structure of communities exposed to PLA-leachate, we found no difference in the relative abundances of gene transcripts associated with plastic degradation. While biodegradable plastics such as PLA may persist for shorter times in the environment than more inert plastics, our study indicates greater consequences for marine microbial communities.

microbiology↗

bioRxiv2022

BDNF stimulates the retrograde pathway for axonal autophagy

Autophagy is a lysosomal degradative pathway important for neuronal development, function, and survival. But how autophagy in axons is regulated by neurotrophins to impact neuronal viability and function is poorly understood. Here, we investigate the regulation of axonal autophagy by the neurotrophin BDNF, and elucidate whether autophagosomes carry BDNF-mediated signaling information. We find that BDNF induces autophagic flux in primary neurons by stimulating the retrograde pathway for autophagy in axons. We observed an increase in autophagosome density and retrograde flux in axons, and a corresponding increase in autophagosome density in the soma. However, we find little evidence of autophagosomes co-migrating with BDNF. In contrast, BDNF effectively engages its cognate receptor TrkB to undergo retrograde transport in the axon. These compartments, however, are distinct from LC3-positive autophagic organelles in the axon. Together, we find that BDNF stimulates autophagy in the axon, but retrograde autophagosomes do not appear to carry neurotrophin-based signaling information. Thus, BDNF likely stimulates autophagy as a consequence of BDNF-induced processes that require canonical roles for autophagy in degradation, rather than unconventional roles in neurotrophin signaling.

neuroscience↗

bioRxiv2022

Retrograde axonal autophagy and endocytic pathways are parallel but separate in neurons

Autophagy and endocytic trafficking are two key pathways that regulate the composition and integrity of the neuronal proteome. Alterations in these pathways are sufficient to cause neurodevelopmental and neurodegenerative disorders. Thus, defining how autophagy and endocytic pathways are organized in neurons remains a key area of investigation. These pathways share many features and converge on lysosomes for cargo degradation, but what remains unclear is the degree to which the identity of each pathway is preserved in each compartment of the neuron. Here, we elucidate the degree of intersection between autophagic and endocytic pathways in axons of primary neurons. Using microfluidic chambers, we labeled newly-generated bulk endosomes and signaling endosomes in the distal axon, and systematically tracked their trajectories, molecular composition, and functional characteristics relative to autophagosomes. We find that newly-formed endosomes and autophagosomes both undergo retrograde transport in the axon, but as distinct organelle populations. Moreover, these pathways differ in their degree of acidification and association with molecular determinants of organelle maturation. These results suggest that the identity of autophagic and newly endocytosed organelles is preserved for the length of the axon. Lastly, we find that expression of a pathogenic form of -synuclein, a protein enriched in presynaptic terminals, increases merging between autophagic and endocytic pathways. Thus, aberrant merging of these pathways may represent a mechanism contributing to neuronal dysfunction in Parkinsons disease and related -synucleinopathies. SIGNIFICANCE STATEMENTAutophagy and endocytic trafficking are retrograde pathways in neuronal axons that fulfill critical degradative and signaling functions. These pathways share many features and converge on lysosomes for cargo degradation, but the extent to which the identity of each pathway is preserved in axons is unclear. We find that autophagosomes and endosomes formed in the distal axon undergo retrograde transport to the soma in parallel but separate pathways. These pathways also have distinct maturation profiles along the mid-axon, further highlighting differences in the potential fate of transported cargo. Strikingly, expression of a pathogenic variant of -synuclein increases merging between autophagic and endocytic pathways, suggesting that mis-sorting of axonal cargo may contribute to neuronal dysfunction in Parkinsons disease and related -synucleinopathies.

neuroscience↗