Biology subjects

Dafsari, H. S.

Publications and source records attributed to Dafsari, H. S..

4 recordsLinked to original sources

bioRxiv2025

Vitamin B12 alleviates Verheij syndrome-like defects via phospholipid remodeling in a C. elegans PUF60 spliceosomopathy model

Verheij syndrome (VRJS) is a rare genetic disorder caused by mutations in the poly(U)-binding splicing factor 60 (PUF60), a core component of the spliceosomal complex. VRJS triggers multiple congenital anomalies, but the underlying pathomechanisms remain poorly understood. Mutation of the Caenorhabditis elegans PUF60 ortholog, rnp-6, recapitulates several hallmarks of VRJS, including growth delay and smaller body size. Here, we demonstrate that developmental defects in rnp-6 mutants are rescued by dietary K12-type Escherichia coli strains. Through complementary genetic screens and multi-omics analyses, we identify vitamin B12 (VB12) as a potent suppressor of these defects, acting via the methionine/S-adenosylmethionine/phosphatidylcholine metabolic axis. Mechanistically, rnp-6 mutation causes aberrant splicing with methionine and phospholipid metabolism-related genes, which cumulatively impair cellular methylation potential, dysregulate phosphatidylcholine metabolism, and induce integrated stress response. We identify intron retention of the nhr-114/HNF4 transcription factor as a primary driver of growth defects, and restoring its splicing robustly suppresses these phenotypes. VB12 supplementation bypasses the aberrant splicing, restores metabolic balance, and activates mTORC1 to rescue developmental phenotypes. Finally, we show that PUF60 deficiency induces aberrant splicing of methionine and phospholipid metabolism-related genes in a human cell line, and is associated with altered plasma methionine and phospholipid levels in VRJS patients. Our findings establish C. elegans as a tractable model for VRJS and uncover SAM/SAH/phospholipid dysregulation as a key mechanism underlying the spliceosomopathy, suggesting VB12 as a potential strategy to mitigate VRJS-related anomalies.

genetics↗

bioRxiv2025

Pathogenic variants in autophagy-tethering factor EPG5 drive neurodegeneration through mitochondrial dysfunction and innate immune activation

The autophagy-tethering factor, ectopic P-granule 5 autophagy protein (EPG5), plays a key role in autophagosome-lysosome fusion. Impaired autophagy associated with pathogenic variants in EPG5 cause a rare devastating multisystem disorder known as Vici syndrome, which includes neurodevelopmental defects, severe progressive neurodegeneration and immunodeficiency. The pathophysiological mechanisms driving disease presentation and progression are not understood. In patient-derived fibroblasts and iPS cells differentiated to cortical neurons, we found that impaired mitophagy leads to mitochondrial bioenergetic dysfunction. Physiological Ca2+ signals resulted in paradoxical mitochondrial Ca2+ overload attributed to downregulation of MICU1/3. Ca2+ signals caused mitochondrial depolarisation, mtDNA release and activation of the cGAS-STING pathway, reversed by pharmacological inhibition of the mitochondrial permeability transition pore (mPTP) or of the STING pathway. Thus, we have identified multiple potential therapeutic targets driving disease progression associated with pathogenic EPG5 mutations, including impaired mitochondrial bioenergetics, mitochondrial Ca2+ overload, vulnerability to mPTP opening and activation of innate immune signalling.

neuroscience↗

bioRxiv2020

Cortical network fingerprint and prediction of stimulation induced speech impairment in essential tremor

ObjectiveTo gain insights into structural networks associated with stimulation-induced dysarthria (SID) and to predict stimulation-induced worsening of intelligibility in essential tremor patients with bilateral thalamic deep brain stimulation (DBS). MethodsMonopolar reviews were conducted in 14 essential tremor patients. Testing included determination of SID thresholds, intelligibility ratings and a fast syllable repetition task. Volumes of tissue activated (VTAs) were calculated to identify discriminative fibers for stimulation-induced worsening of intelligibility in a structural connectome. The resulting fiber-based atlas structure was than validated in a leave-one-out design. ResultsFibers determined as discriminative for stimulation-induced worsening of intelligibility were mainly connected to the ipsilateral precentral gyrus as well as to both cerebellar hemispheres and the ipsilateral brainstem. In the thalamic area, they ran laterally to the thalamus and postero-medially to the subthalamic nucleus, in close proximity, mainly antero-laterally, to fibers beneficial for tremor control as published by Al-Fatly et al. (2019). The overlap of the respective clinical stimulation settings VTAs with these fibers explained 62.4% (p<0.001) of the variance of stimulation-induced change in intelligibility in a leave-one out analysis. InterpretationThis study demonstrates that SID in essential tremor patients is associated with both, motor cortex and cerebellar connectivity. Furthermore, the identified fiber-based atlas structure might contribute to future postoperative programming strategies to achieve optimal tremor control without speech impairment in ET patients with thalamic DBS.

neuroscience↗

bioRxiv2019

Directional DBS Leads Show Large Deviations from their Intended Implantation Orientation

ObjectiveLead orientation is a new degree of freedom with directional deep brain stimulation (DBS) leads. We investigated how prevalent deviations from the intended implantation direction are in a large patient cohort.\n\nMethodsThe Directional Orientation Detection (DiODe) algorithm to determine lead orientation from postoperative CT scans was implemented into the open-source Lead-DBS toolbox. Lead orientation was analysed in 100 consecutive patients (198 leads). Different anatomical targets and intraoperative setups were compared.\n\nResultsDeviations of up to 90{degrees} from the intended implantation direction were observed. Deviations of more than 30{degrees} were seen in 42 % of the leads and deviations of more than 60{degrees} in about 11 % of the leads. Deviations were independent from the neuroanatomical target and the stereotactic frame but increased depending on which microdrive was used.\n\nDiscussionOur results indicate that large deviations from the intended implantation direction are a common phenomenon in directional leads. Postoperative determination of lead orientation is thus mandatory for investigating directional DBS.\n\nFull DisclosuresTill A. Dembek reports speaker honoraria from Medtronic and Boston Scientific.\n\nMauritius Hoevels has nothing to disclose.\n\nAlexandra Hellerbach has nothing to disclose.\n\nAndreas Horn reports speaker honoraria from Medtronic.\n\nJan Niklas Petry-Schmelzer reports travel grants from Boston Scientific.\n\nJan Borggrefe has nothing to disclose.\n\nJochen Wirths reports travel grants from Boston Scientific.\n\nHaidar Salimi-Dafsari reports honoraria from Medtronic and Boston Scientific.\n\nMichael T. Barbe reports grants from Medtronic and Boston Scientific.\n\nVeerle Visser-Vandewalle is a member of the advisory boards and reports consultancies for Medtronic, Boston Scientific and St Jude Medical. She received a grant from SAPIENS Steering Brain Stimulation. Harald Treuer has nothing to disclose.

neuroscience↗