Sokhna Haissatou Diaw

University of Lübeck

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i-10 index

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Co-Authors

Katja Lohmann

University of Lübeck

Christine Klein

University of Lübeck

Marija Dulovic‐Mahlow

University of Lübeck

Alexander Münchau

University of Lübeck

Philip Seibler

University of Lübeck

Melissa Vos

University of Lübeck

Max Borsche

University of Lübeck

Simone Zittel

Universität Hamburg

Fabian Ott

University of Lübeck

Insa Lenz

University of Lübeck

Cooperative Institutions

University of Lübeck

University Hospital Schleswig-Holstein

John Wiley & Sons (United States)

University College London

Universität Hamburg

National Hospital for Neurology and Neurosurgery

University Medical Center

University of Belgrade

University of the Philippines Manila

Ljubljana University Medical Centre

Author Statistics

Papers

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Emerging role of a systems biology approach to elucidate factors of reduced penetrance: transcriptional changes in THAP1-linked dystonia as an example

Medizinische Genetik (2022)

Sokhna Haissatou Diaw Fabian Ott Alexander Münchau Katja Lohmann Hauke Busch

Abstract Pathogenic variants in THAP1 can cause dystonia with a penetrance of about 50 %. The underlying mechanisms are unknown and can be considered as means of endogenous disease protection. Since THAP1 encodes a transcription factor, drivers of this variability putatively act at the transcriptome level. Several transcriptome studies tried to elucidate THAP1 function in diverse cellular and mouse models, including mutation carrier-derived cells and iPSC-derived neurons, unveiling various differentially expressed genes and affected pathways. These include nervous system development, dopamine signalling, myelination, or cell-cell adhesion. A network diffusion analysis revealed mRNA splicing, mitochondria, DNA repair, and metabolism as significant pathways that may represent potential targets for therapeutic interventions.

Penetrance

Exon skipping

10.1515/medgen-2022-2126

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Citations (2)

The Expanding Phenotypical Spectrum of WARS2-Related Disorder: Four Novel Cases with a Common Recurrent Variant

Genes (2023)

Martje G. Pauly Georg-Christoph Korenke Sokhna Haissatou Diaw Anne Grözinger Ana Cazurro‐Gutiérrez

Biallelic variants in the mitochondrial form of the tryptophanyl-tRNA synthetases (WARS2) can cause a neurodevelopmental disorder with movement disorders including early-onset tremor–parkinsonism syndrome. Here, we describe four new patients, who all presented at a young age with a tremor–parkinsonism syndrome and responded well to levodopa. All patients carry the same recurrent, hypomorphic missense variant (NM_015836.4: c.37T>G; p.Trp13Gly) either together with a previously described truncating variant (NM_015836.4: c.797Cdel; p.Pro266ArgfsTer10), a novel truncating variant (NM_015836.4: c.346C>T; p.Gln116Ter), a novel canonical splice site variant (NM_015836.4: c.349-1G>A), or a novel missense variant (NM_015836.4: c.475A>C, p.Thr159Pro). We investigated the mitochondrial function in patients and found increased levels of mitochondrially encoded cytochrome C Oxidase II as part of the mitochondrial respiratory chain as well as decreased mitochondrial integrity and branching. Finally, we conducted a literature review and here summarize the broad phenotypical spectrum of reported WARS2-related disorders. In conclusion, WARS2-related disorders are diagnostically challenging diseases due to the broad phenotypic spectrum and the disease relevance of a relatively common missense change that is often filtered out in a diagnostic setting since it occurs in ~0.5% of the general European population.

Mitochondrial disease

Compound heterozygosity

10.3390/genes14040822

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Citations (2)

Ceramide accumulation induces mitophagy and impairs β-oxidation in PINK1 deficiency

Proceedings of the National Academy of Sciences (2021)

Melissa Vos Marija Dulovic‐Mahlow Frida Mandik Lisa Frese Yuliia Kanana

Significance Ceramide accumulates in Parkinson’s disease–related PINK1 deficiency to initiate ceramide-mediated mitophagy as an alternative pathway to overcome defective PINK1-related mitophagy and the concomitant increased requirements for mitochondrial clearance. Increased ceramide levels negatively correlate with β-oxidation and thus decrease efficiency of the electron transport chain, further increasing the need for mitochondrial clearance. Interfering with this vicious cycle can constitute a novel therapeutic strategy as suggested by our data showing that a reduction of ceramide levels or stimulation of β-oxidation improve the PINK1 -mutant phenotypes.

PINK1

Ceramide synthase

10.1073/pnas.2025347118

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Citations (54)

Discordant Monozygotic Parkinson Disease Twins: Role of Mitochondrial Integrity

Annals of Neurology (2020)

Marija Dulovic‐Mahlow Inke R. König Joanne Trinh Sokhna Haissatou Diaw Péter Urbán

Even though genetic predisposition has proven to be an important element in Parkinson's disease (PD) etiology, monozygotic (MZ) twins with PD displayed a concordance rate of only about 20% despite their shared identical genetic background.We recruited 5 pairs of MZ twins discordant for idiopathic PD and established skin fibroblast cultures to investigate mitochondrial phenotypes in these cellular models against the background of a presumably identical genome. To test for genetic differences, we performed whole genome sequencing, deep mitochondrial DNA (mtDNA) sequencing, and tested for mitochondrial deletions by multiplex real-time polymerase chain reaction (PCR) in the fibroblast cultures. Further, the fibroblast cultures were tested for mitochondrial integrity by immunocytochemistry, immunoblotting, flow cytometry, and real-time PCR to quantify gene expression.Genome sequencing did not identify any genetic difference. We found decreased mitochondrial functionality with reduced cellular adenosine triphosphate (ATP) levels, altered mitochondrial morphology, elevated protein levels of superoxide dismutase 2 (SOD2), and increased levels of peroxisome proliferator-activated receptor-gamma coactivator-α (PPARGC1A) messenger RNA (mRNA) in skin fibroblast cultures from the affected compared to the unaffected twins. Further, there was a tendency for a higher number of somatic mtDNA variants among the affected twins.We demonstrate disease-related differences in mitochondrial integrity in the genetically identical twins. Of note, the clinical expression matches functional alterations of the mitochondria. ANN NEUROL 2021;89:158-164.

Monozygotic twin

Mitochondrial disease

10.1002/ana.25942

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Citations (13)

Generation and characterization of human-derived iPSC lines from three pairs of monozygotic twins discordant for Parkinson's disease

Stem Cell Research (2019)

Marija Dulovic‐Mahlow Agnieszka Łukomska Sokhna Haissatou Diaw Alexander Balck Max Borsche

Despite a genetic component in the development of Parkinson's disease (PD), monozygotic twin pairs often display discordance for PD. Here, we describe the generation of six human induced pluripotent stem cell (iPSC) lines from dermal fibroblasts of three pairs of monozygotic twins discordant for PD. We used non-integrating Sendai virus and the iPSC lines were comprehensively characterized. These lines provide a valuable resource for studying molecular differences between the affected and unaffected monozygotic twin and their response to genetic and non-genetic factors that might be involved in the development of PD.

Sendai virus

Monozygotic twin

Human disease

10.1016/j.scr.2019.101629

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Citations (1)

Linking Huntington's Disease and X‐linked Dystonia Parkinsonism on the Molecular Level

Movement Disorders (2020)

Sokhna Haissatou Diaw Katja Lohmann

Hernández IH, Cabrera JR, Santos-Galindo M, et al. Pathogenic SREK1 decrease in Huntington's disease lowers TAF1 mimicking X-linked dystonia parkinsonism. Brain 2020; 143(7):2207–2219. Huntington's disease (HD) and X-linked dystonia parkinsonism (XDP) are two monogenic, neurodegenerative movement disorders with an origin in the striatum.1, 2 Both conditions also share clinical features (chorea and dystonia) and the involvement of a repeat expansion in the disease mechanism. Whereas HD is caused by a polyglutamine-encoding CAG repeat expansion in the Huntingtin (HTT) gene, XDP is caused by a retrotransposon (SINE-VNTR-Alu [SVA]) insertion in the TATA-box binding protein associated factor 1 (TAF1) gene that contains a disease-modifying hexanucleotide repeat.3 Using cell lines, striatum of HD patients, and a HD mouse model, Hernandez and colleagues4 demonstrated that the clinical overlap of HD and XDP also has a molecular equivalent, namely decreased TAF1 expression, which is in HD mediated by altered RNA processing on SREK1 dysregulation because of modified SRSF6 levels and/or activity (Fig. 1). SREK1 is a member of the serine/arginine-rich (SR) protein family and as an RNA binding protein (RBP) involved in RNA processing including TAF1 as a target. Moreover, SREK1 is a direct interactor and regulator of SRSF6, a splicing factor involved in HTT pre-mRNA constitutive and alternative splicing as an RBP. SRSF6 promotes pathogenic mis-splicing events in HTT and, thereby, HTT aggregation and toxicity. Interaction of SRSF6 with HTT-inclusion bodies and sequestration of SRSF6 and other RBPs into RNA foci deteriorates the situation. Importantly, Hernandez and colleagues4 performed a rescue experiment by overexpressing SREK1 in the transgenic HD mouse model. Interestingly, these mice, at least in early stages, showed opposite transcriptomic changes compared to those in unmodified HD mice, indicating that SREK1 overexpression may correct TAF1 deficiency and attenuates striatal atrophy and motor phenotype in HD, and by this pointing to a novel, potential therapeutic strategy.4 On the other hand, SREK1 has many targets and expressional changes other than of TAF1 may be relevant in patients and need to be taken into account when considering SREK1 overexpression as a therapy. The fact that missense variants in and partial duplications of TAF1 lead to a severe neurodevelopmental disorder5 underlines that TAF1 expression needs to be tightly regulated. It also remains to be addressed if alteration of TAF1 expression in HD contributes to the pathogenesis or is a consequence. The contributing role of repeat-containing mRNA in disease pathogenesis suggests that HD and XDP are part of a growing list of molecularly linked neurodegenerative disorders associated with RNA-mediated toxicity. Of note, reversing RNA aberrations could modify the incessantly downward disease trajectory. Manuscript Preparation: A. Writing the First Draft, B. Review and Critique. S.H.D.: 1A K.L.: 1A S.H.D. received a grant from ERASMUS scholarship. K.L. received grants from the German Research Foundation, the Movement Disorder Society, and Damp-Stiftung and is employed by the University of Lübeck.

10.1002/mds.28287

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Citations (1)

Not to Miss: Intronic Variants, Treatment, and Review of the Phenotypic Spectrum in VPS13D-Related Disorder

International Journal of Molecular Sciences (2023)

Martje G. Pauly Norbert Brüggemann Stéphanie Efthymiou Anne Grözinger Sokhna Haissatou Diaw

VPS13D is one of four human homologs of the vacuolar sorting protein 13 gene (VPS13). Biallelic pathogenic variants in the gene are associated with spastic ataxia or spastic paraplegia. Here, we report two patients with intronic pathogenic variants: one patient with early onset severe spastic ataxia and debilitating tremor, which is compound-heterozygous for a canonical (NM_018156.4: c.2237−1G > A) and a non-canonical (NM_018156.4: c.941+3G>A) splice site variant. The second patient carries the same non-canonical splice site variant in the homozygous state and is affected by late-onset spastic paraplegia. We confirmed altered splicing as a result of the intronic variants and demonstrated disturbed mitochondrial integrity. Notably, tremor in the first patient improved significantly by bilateral deep brain stimulation (DBS) in the ventralis intermedius (VIM) nucleus of the thalamus. We also conducted a literature review and summarized the phenotypical spectrum of reported VPS13D-related disorders. Our study underscores that looking for mutations outside the canonical splice sites is important not to miss a genetic diagnosis, especially in disorders with a highly heterogeneous presentation without specific red flags.

Hereditary Spastic Paraplegia

splice

Splice site mutation

Movement Disorders

10.3390/ijms24031874

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Citations (13)

Mutant WDR45 Leads to Altered Ferritinophagy and Ferroptosis in β-Propeller Protein-Associated Neurodegeneration

International Journal of Molecular Sciences (2022)

Sokhna Haissatou Diaw Christos Ganos Simone Zittel Kirstin Plötze‐Martin Leonora Kulikovskaja

Beta-propeller protein-associated neurodegeneration (BPAN) is a subtype of neurodegeneration with brain iron accumulation (NBIA) caused by loss-of-function variants in WDR45. The underlying mechanism of iron accumulation in WDR45 deficiency remains elusive. We established a primary skin fibroblast culture of a new BPAN patient with a missense variant p.(Asn61Lys) in WDR45 (NM_007075.3: c.183C>A). The female patient has generalized dystonia, anarthria, parkinsonism, spasticity, stereotypies, and a distinctive cranial MRI with generalized brain atrophy, predominantly of the cerebellum. For the functional characterization of this variant and to provide a molecular link of WDR45 and iron accumulation, we looked for disease- and variant-related changes in the patient’s fibroblasts by qPCR, immunoblotting and immunofluorescence comparing to three controls and a previously reported WDR45 patient. We demonstrated molecular changes in mutant cells comprising an impaired mitochondrial network, decreased levels of lysosomal proteins and enzymes, and altered autophagy, confirming the pathogenicity of the variant. Compared to increased levels of the ferritinophagy marker Nuclear Coactivator 4 (NCOA4) in control cells upon iron treatment, patients’ cells revealed unchanged NCOA4 protein levels, indicating disturbed ferritinophagy. Additionally, we observed abnormal protein levels of markers of the iron-dependent cell death ferroptosis in patients’ cells. Altogether, our data suggests that WDR45 deficiency affects ferritinophagy and ferroptosis, consequentially disturbing iron recycling.

10.3390/ijms23179524

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Citations (17)

Characterization of the pathogenic α-Synuclein Variant V15A in Parkinson´s disease

npj Parkinson s Disease (2023)

Sokhna Haissatou Diaw Max Borsche Linn Streubel-Gallasch Marija Dulovic‐Mahlow Júlia Hermes

Despite being a major component of Lewy bodies and Lewy neurites, pathogenic variants in the gene encoding alpha-Synuclein (α-Syn) are rare. To date, only four missense variants in the SNCA gene, encoding α-Syn have unequivocally been shown to be disease-causing. We here describe a Parkinson´s disease patient with early cognitive decline carrying an as yet not fully characterized variant in SNCA (NM_001146055: c.44T > C, p.V15A). We used different cellular models, including stably transfected neuroblastoma (SH-SY5Y) cell cultures, induced pluripotent stem cell (iPSC)-derived neuronal cultures, and generated a Drosophila model to elucidate the impact of the p.V15A variant on α-Syn function and aggregation properties compared to other known pathogenic variants. We demonstrate that p.V15A increased the aggregation potential of α-Syn and the levels of apoptotic markers, and impaired the mitochondrial network. Moreover, p.V15A affects the flying ability and survival of mutant flies. Thus, we provide supporting evidence for the pathogenicity of the p.V15A variant, suggesting its inclusion in genetic testing approaches.

Neurite

10.1038/s41531-023-00584-z

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Citations (5)

DYT-THAP1: exploring gene expression in fibroblasts for potential biomarker discovery

Neurogenetics (2024)

Sokhna Haissatou Diaw Sylvie Delcambre Christoph Much Fabian Ott Vladimir Kostić

Penetrance

10.1007/s10048-024-00752-0

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Citations (1)