Biology subjects

Raza, S. A.

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

3 recordsLinked to original sources

bioRxiv2025

Maintenance of chronic neuroinflammation in multiple sclerosis via interferon signaling and CD8 T cell-mediated cytotoxicity

Chronic neuroinflammation and neurodegeneration are critical but unresolved drivers of disability accumulation in progressive multiple sclerosis (MS). Chronic active white matter lesions (CAL), identifiable radiologically as paramagnetic rim lesions (PRL), indicate progression-relevant chronic neuroinflammation. Using single-cell transcriptomics (scRNAseq) and T-cell receptor sequencing (scTCR-seq), we profiled cerebrospinal fluid (CSF) and blood immune cells of 34 radiologically characterized adults with MS (17 untreated, 6 treated with B-cell-depletion) and 5 healthy controls. Coupled with proteomics, we found PRL-associated enrichment of interferon (IFN) signaling and upregulation of TCR signaling in CSF and blood. This was accompanied by clonal expansion of CD8+ T effector memory (TEM) cells, with the highly expanded clonal cells exhibiting T helper type 1 (TH1) and cytotoxic profiles. Validating the cytotoxic immune profile in blood using flow cytometry, we identified a cellular correlate of PRL exhibiting features of CD8+ TEMRA cells. Despite B-cell depletion, PRL-associated neuroinflammation, driven by myeloid activation and CD8+ T-cell cytotoxicity, persisted. Serum and CSF proteomic networks showed PRL-pertinent signatures, including networks unaffected by B-cell depletion. Using in silico perturbation, we nominated therapeutic targets, including MYD88, TNF, MYC, TYK2, JAK2, and BTK, for alleviating chronic neuroinflammation in MS. Our findings highlight mechanisms of chronic neuroinflammation in MS and point to potential biomarkers for monitoring disease progression.

immunology↗

bioRxiv2022

Fear engrams and NPYergic circuit in the dorsal dentate gyrus determine remote fear memory generalization.

Generalization is a critical feature of aversive memories and significantly contributes to post-traumatic stress disorder (PTSD) pathogenesis. While fear memories over time tend to generalize across differences in the contextual background and even to novel contextual settings, this effect can be counteracted by exposure to controlled reminder sessions even at remote time points. Using Pavlovian fear conditioning in mice, we show that generalization to a novel context of remote memory is associated with a loss of cellular engram activation in the dorsal dentate gyrus (dDG) and can be effectively counteracted by a preceding contextual reminder session. In addition to engram cells activation in response to a novel context, the reminder session also leads to a recovery of neuropeptide Y (NPY) function in the dDG and dDG-CA3 neurotransmission. In line with a proposed role of NPY as a resilience factor, we found that chronic viral knockdown of NPY in the dDG and blockage of its activity-dependent expression in NPYergic dDG interneurons with dominant-negative CREBS133A both increase remote memory generalization. With chemogenetic silencing of these interneurons, we could localize their critical involvement to a time window during and immediately following the fear memory acquisition. Together, these findings suggest that NPYergic interneurons of the dDG, shaping the memory engram during fear learning and early consolidation, determine fear generalization.

neuroscience↗

bioRxiv2019

SIPA1L2 controls trafficking and signaling of TrkB-containing amphisomes at presynaptic terminals

Amphisomes are transient organelles that derive from fusion of autophagosomes with late endosomes. They rapidly transform into degradative autolysosomes, whereas non-degradative roles of the autophagic pathway have been barely described. Here we show that in neurons BDNF/TrkB receptor bearing Rab7 / Light chain 3 (LC3) - positive amphisomes signal at presynaptic boutons during retrograde trafficking to the soma. Local signaling and inward transport essentially require the Rap GTPase-activating (RapGAP) protein SIPA1L2, which directly binds to TrkB and Snapin to connect TrkB-containing amphisomes to dynein. Association with LC3 regulates the RapGAP activity of SIPA1L2 and thereby retrograde trafficking. Following induction of presynaptic plasticity amphisomes dissociate from dynein at boutons, and this enables local signaling and promotes transmitter release. Accordingly, sipa1l2 knockout mice show impaired BDNF-dependent presynaptic plasticity. Collectively, the data suggest that TrkB-signaling endosomes are in fact amphisomes that during retrograde transport have local signaling capacity in the context of presynaptic plasticity.

neuroscience↗