VPS41 recessive mutation causes ataxia and dystonia with retinal dystrophy and mental retardation by inhibiting HOPS function and mTORC1 signaling

van der Welle, R. E. N.; Jobling, R.; Burns, C.; Sanza, P.; ten Brink, C.; Fasano, A.; Chen, L.; Zwartkruis, F. J.; Zwakenberg, S.; Griffin, E. F.; van der Beek, J.; Veenendaal, T.; Liv, N.; Blaser, S.; Sepulveda, C.; Lozano, A. M.; Yoon, G.; Asensio, C. S.; Caldwell, G. A.; Caldwell, K. A.; Chitayat, D.; Klumperman, J.

doi:10.1101/2019.12.18.867333

Home/Archive/bioRxiv

bioRxiv · 10.1101/2019.12.18.867333

VPS41 recessive mutation causes ataxia and dystonia with retinal dystrophy and mental retardation by inhibiting HOPS function and mTORC1 signaling

View original source ↗Export metadata ↓

Abstract

The vacuolar protein sorting protein 41 (VPS41) is a neuroprotective protein in models of Parkinsons disease (PD). As part of the HOPS (Homotypic fusion and Protein Sorting) complex, VPS41 regulates fusion of lysosomes with late endosomes and autophagosomes. Independent of HOPS, VPS41 regulates transport of newly synthesized lysosomal membrane proteins and secretory proteins. Here we report two brothers with compound heterozygous mutations in VPS41 (VPS41R662* and VPS41S285P), born to healthy and non-consanguineous parents. Both patients displayed transient retinal dystrophy, ataxia and dystonia, with brain MRI findings of cerebellar atrophy and a thin saber-shape corpus callosum. Patient-derived fibroblasts contained enzymatically active lysosomes that were poorly reached by endocytic cargo and failed to attract the mTORC1 complex. Consequently, transcription factor TFE3, a driver of autophagy and lysosomal genes, showed continuous nuclear localization which resulted in elevated LC3-II levels and an impaired response to nutrient starvation. CRISPR/CAS VPS41 HeLa knockout cells showed a similar phenotype that could be rescued by wildtype VPS41 but not by VPS41S285P or VPS41R662*. mTORC1 inhibition was also seen after knockout of HOPS subunits VPS11 or VPS18. Regulated neuropeptide secretion in PC12 VPS41 knockout cells was rescued by VPS41S285P expression, indicating that this HOPS-independent function was preserved. Co-expression of the VPS41S285P and VPS41R662* variants in a C. elegans model of PD abolished the protective effect of VPS41 against -synuclein-induced neurodegeneration. We conclude that both disease-associated VPS41 variants specifically abrogate HOPS function, which leads to a delay in endocytic cargo delivery to lysosomes, mTORC1 inhibition and irresponsiveness to autophagic clues. Our studies signify a link between HOPS function and mTORC1 signaling and imply that HOPS function is required for the neuroprotective effect of VPS41 in PD.

Explore related subjects

cell biology Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

van der Welle, R. E. N., Jobling, R., Burns, C., Sanza, P., ten Brink, C., Fasano, A., Chen, L., Zwartkruis, F. J., Zwakenberg, S., Griffin, E. F., van der Beek, J., Veenendaal, T., Liv, N., Blaser, S., Sepulveda, C., Lozano, A. M., Yoon, G., Asensio, C. S., Caldwell, G. A., Caldwell, K. A., Chitayat, D., Klumperman, J.. 2019-12-20. VPS41 recessive mutation causes ataxia and dystonia with retinal dystrophy and mental retardation by inhibiting HOPS function and mTORC1 signaling. https://doi.org/10.1101/2019.12.18.867333

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Sequential pathways preserve kinetochore integrity in meiosis

Kinetochores connect chromosomes to spindle microtubules, but how their integrity is maintained as they are remodelled during meiosis remains poorly understood. Here, we identify three distinct pathways linking centromeric chromatin to the outer kinetochore in budding yeast, mediated by the Ctf19 complex (Ctf19cCCAN), Mif2CENP-C and binding of Okp1CENP-Q-Ame1CENP-U to the Cse4CENP-A essential N-terminal domain (END). Although partially redundant during mitosis, all three connections are required during meiosis, with distinct temporal requirements. The assembled Ctf19cCCAN and Mif2CENP-C-dependent pathways maintain kinetochore integrity from meiotic entry, while Cse4CENP-A-Okp1CENP-Q-Ame1CENP-U binding becomes critical during prophase and the meiotic divisions. We further show that Ipl1Aurora B maintains kinetochore integrity independently of Ctf19cCCAN and provide evidence for an outer kinetochore-associated Ipl1Aurora B pool. Strikingly, Cse4CENP-A phosphomimetic mutations that restore kinetochore integrity upon Ipl1Aurora B depletion instead exacerbate defects in cells lacking Ctf19cCCAN. Our findings suggest that phosphorylation of the Cse4CENP-A N-terminal domain (NTD) by Ipl1Aurora B may regulate the use of alternative centromere-kinetochore connections to adapt to the changing requirements of meiosis.

cell biology↗

bioRxiv2026

Endothelial Cell Specific Thioredoxin 1-Dependent Signaling in Oxygen-1 Induced Retinopathy

Purpose: Retinopathy of prematurity (ROP) is a leading cause of childhood blindness, characterized byoxidative stress and dysregulated angiogenesis in preterm infants with immature antioxidant systems.This study aimed to investigate the specific role of endothelial cell-specific thioredoxin 1 (TXN1), a crucial oxidoreductase, in oxygen-induced retinopathy, hypothesizing that the absence of endothelial TXN1 directly impairs angiogenesis and exacerbates hyperoxia-induced injury. Methods: We generated tamoxifen-inducible, endothelial cell-specific Txn1 knockout mice (Txn1-iECKO) and utilized the oxygen-induced retinopathy (OIR) model, exposing litters to 85% oxygen from postnatal day 7 (P7) to P12. Retinal vascular morphology during vaso-obliteration and neovascularization phases, endothelial cell proliferation, and apoptotic cell death were assessed. Furthermore, human retinal microvascular endothelial cells (HRMECs) with TXN1 knockdown were subjected to hyperoxic conditions, followed by comprehensive gene expression profiling using RT2 Profiler PCR arrays and Ingenuity Pathway Analysis. Results: Deletion of endothelial Txn1 significantly enhanced vascular regression during the hyperoxic vaso-obliteration phase at P12 and markedly exacerbated pathological neovascularization at P17. Txn1-deficient retinas exhibited significantly impaired endothelial cell proliferation during the vaso-obliteration phase, while apoptotic cell death remained unchanged. Transcriptomic analysis of TXN1-deficient HRMECs under hyperoxia revealed an enhanced activation of NRF2-mediated oxidative stress response pathways. Conclusions: These findings identify endothelial TXN1 as an essential and oxygen-dependent regulator of vascular development in ischemic retinopathy, primarily influencing endothelial proliferation and redox signaling. This suggests TXN1's crucial protective role and highlights its therapeutic potential to mitigate ROP progression by modulating endothelial cell responses to oxidative stress.

cell biology↗

bioRxiv2026

A Dynamic Stem Cell State Links Environmental Cues to Skeletal and Regenerative Fates

Stem cells faithfully generate tissue architecture during development, yet how their identity and regenerative output are reshaped as anatomical niches mature and environmental signals change with aging and injury remains poorly understood. Rare skeletal stem cells (SSCs) across diverse skeletal sites are defined by combinations of cell-surface markers, precluding their genetic interrogation in vivo. Here, using spatially informed single cell transcriptomics, we identify Pannexin-3 (Panx3) to mark a dynamic functional state within bona fide SSCs and establish Panx3-CreERT2 mice for its longitudinal interrogation. Panx3 SSCs exhibit long-term clonal persistence, self-renewal and multipotency, whereas Panx3- SSCs can acquire this state. Successive SSC cohorts engage the Panx3 state during skeletal development, osteoanabolic stimulation expands pre-existing Panx3 SSC clones and injury induces it locally in previously unlabeled progenitors. Thus, anatomically distinct progenitors can converge on a common stem cell state in response to different environmental inputs. Three-dimensional reconstruction of chondrogenic niches further identifies signals that redirect Panx3-lineage cells towards stable cartilage, enabling durable regeneration in aged and osteoarthritic joints and with human SSCs. These findings establish anatomical origin, stem cell state and lineage fate as separable dimensions of stem cell identity and provide genetic access for interrogating and directing endogenous SSC function.

cell biology↗