Biology subjects

Mane, S.

Publications and source records attributed to Mane, S..

4 recordsLinked to original sources

bioRxiv2026

Variant-Specific Rewiring of Lysosomal Positioning by STARD9 Produces Opposite Cholesterol Trafficking Outcomes

Residual cardiovascular risk persists despite lipid-lowering therapy, independent of LDL and Lp(a), reflecting cholesterol dysregulation. We identify STARD9, a lysosomal cholesterol-sensing kinesin, as a causal gene for divergent familial dyslipidemias and premature atherosclerosis. Its START domain binds cholesterol to govern lysosomal positioning. Rare variants segregate with autosomal dominant hypercholesterolemia and premature coronary disease, while common variants associate with reduced HDL and elevated triglycerides. Both converge on lysosomal cholesterol sequestration, ER depletion, mTORC1 SREBP2 activation, impaired autophagy, and NF-kB inflammation, yet diverge through opposite lysosomal positioning: the rare variant disperses lysosomes peripherally, phenocopying START domain loss across cholesterol sequestration, lysosomal positioning, and TFEB activation, triggering LDLR degradation and CASM/TFEB-dependent efflux that preserves HDL, whereas the common variant causes perinuclear retention that suppresses TFEB dependent lipid-handling transcripts, yielding hypertriglyceridemia and low HDL. In Stard9-knockout mice, enterocyte cholesterol sequestration drives SREBP2 dependent NPC1L1 upregulation and apical localization, increasing intestinal cholesterol absorption. These findings position lysosomal cholesterol trafficking as a targetable node in statin-refractory cardiovascular disease.

genetics↗

bioRxiv2023

Genetic dysregulation of an endothelial Ras signaling network in vein of Galen malformations

To elucidate the pathogenesis of vein of Galen malformations (VOGMs), the most common and severe congenital brain arteriovenous malformation, we performed an integrated analysis of 310 VOGM proband-family exomes and 336,326 human cerebrovasculature single-cell transcriptomes. We found the Ras suppressor p120 RasGAP (RASA1) harbored a genome-wide significant burden of loss-of-function de novo variants (p=4.79x10-7). Rare, damaging transmitted variants were enriched in Ephrin receptor-B4 (EPHB4) (p=1.22x10-5), which cooperates with p120 RasGAP to limit Ras activation. Other probands had pathogenic variants in ACVRL1, NOTCH1, ITGB1, and PTPN11. ACVRL1 variants were also identified in a multi-generational VOGM pedigree. Integrative genomics defined developing endothelial cells as a key spatio-temporal locus of VOGM pathophysiology. Mice expressing a VOGM-specific EPHB4 kinase-domain missense variant exhibited constitutive endothelial Ras/ERK/MAPK activation and impaired hierarchical development of angiogenesis-regulated arterial-capillary-venous networks, but only when carrying a "second-hit" allele. These results illuminate human arterio-venous development and VOGM pathobiology and have clinical implications.

genomics↗

bioRxiv2023

LRRC23 loss-of-function impairs radial spoke 3 head assembly and causes defective sperm motility underlying male infertility

Radial spokes (RS) are T-shaped multiprotein complexes on the axonemal microtubules. Repeated RS1, RS2, and RS3 couple the central pair to modulate ciliary and flagellar motility. Despite the cell type specificity of RS3 substructures, their molecular components remain largely unknown. Here, we report that a leucine-rich repeat-containing protein, LRRC23, is an RS3 head component essential for its head assembly and flagellar motility in mammalian spermatozoa. From infertile male patients with defective sperm motility, we identified a splice site variant of LRRC23. A mutant mouse model mimicking this variant produces a truncated LRRC23 at the C-terminus that fails to localize to the sperm tail, causing male infertility due to defective sperm motility. LRRC23 was previously proposed to be an ortholog of the RS stalk protein RSP15. However, we found that purified recombinant LRRC23 interacts with an RS head protein RSPH9, which is abolished by the C-terminal truncation. Evolutionary and structural comparison also shows that LRRC34, not LRRC23, is the RSP15 ortholog. Cryo-electron tomography clearly revealed that the absence of the RS3 head and the sperm-specific RS2-RS3 bridge structure in LRRC23 mutant spermatozoa. Our study provides new insights into the structure and function of RS3 in mammalian spermatozoa and the molecular pathogenicity of LRRC23 underlying reduced sperm motility in infertile human males.

cell biology↗

bioRxiv2020

Neuroinvasive potential of SARS-CoV-2 revealed in a human brain organoid model

Although COVID-19 is considered to be primarily a respiratory disease, SARS-CoV-2 affects multiple organ systems including the central nervous system (CNS). Yet, there is no consensus whether the virus can infect the brain, or what the consequences of CNS infection are. Here, we used three independent approaches to probe the capacity of SARS-CoV-2 to infect the brain. First, using human brain organoids, we observed clear evidence of infection with accompanying metabolic changes in the infected and neighboring neurons. However, no evidence for the type I interferon responses was detected. We demonstrate that neuronal infection can be prevented either by blocking ACE2 with antibodies or by administering cerebrospinal fluid from a COVID-19 patient. Second, using mice overexpressing human ACE2, we demonstrate in vivo that SARS-CoV-2 neuroinvasion, but not respiratory infection, is associated with mortality. Finally, in brain autopsy from patients who died of COVID-19, we detect SARS-CoV-2 in the cortical neurons, and note pathologic features associated with infection with minimal immune cell infiltrates. These results provide evidence for the neuroinvasive capacity of SARS-CoV2, and an unexpected consequence of direct infection of neurons by SARS-CoV-2.

microbiology↗