SwePub
Sök i SwePub databas

  Utökad sökning

Träfflista för sökning "WFRF:(Puschmann Andreas) "

Sökning: WFRF:(Puschmann Andreas)

  • Resultat 11-20 av 99
Sortera/gruppera träfflistan
   
NumreringReferensOmslagsbildHitta
11.
  • Fiesel, Fabienne C., et al. (författare)
  • Substitution of PINK1 Gly411 modulates substrate receptivity and turnover
  • 2023
  • Ingår i: Autophagy. - : Informa UK Limited. - 1554-8627 .- 1554-8635. ; 19:6, s. 1711-1732
  • Tidskriftsartikel (refereegranskat)abstract
    • The ubiquitin (Ub) kinase-ligase pair PINK1-PRKN mediates the degradation of damaged mitochondria by macroautophagy/autophagy (mitophagy). PINK1 surveils mitochondria and upon stress accumulates on the mitochondrial surface where it phosphorylates serine 65 of Ub to activate PRKN and to drive mitochondrial turnover. While loss of either PINK1 or PRKN is genetically linked to Parkinson disease (PD) and activating the pathway seems to have great therapeutic potential, there is no formal proof that stimulation of mitophagy is always beneficial. Here we used biochemical and cell biological methods to study single nucleotide variants in the activation loop of PINK1 to modulate the enzymatic function of this kinase. Structural modeling and in vitro kinase assays were used to investigate the molecular mechanism of the PINK1 variants. In contrast to the PD-linked PINK1G411S mutation that diminishes Ub kinase activity, we found that the PINK1G411A variant significantly boosted Ub phosphorylation beyond levels of PINK1 wild type. This resulted in augmented PRKN activation, mitophagy rates and increased viability after mitochondrial stress in midbrain-derived, gene-edited neurons. Mechanistically, the G411A variant stabilizes the kinase fold of PINK1 and transforms Ub to adopt the preferred, C-terminally retracted conformation for improved substrate turnover. In summary, we identify a critical role of residue 411 for substrate receptivity that may now be exploited for drug discovery to increase the enzymatic function of PINK1. The genetic substitution of Gly411 to Ala increases mitophagy and may be useful to confirm neuroprotection in vivo and might serve as a critical positive control during therapeutic development. Abbreviations: ATP: adenosine triphosphate; CCCP: carbonyl cyanide m-chlorophenyl hydrazone; Ub-CR: ubiquitin with C-terminally retracted tail; CTD: C-terminal domain (of PINK1); ELISA: enzyme-linked immunosorbent assay; HCI: high-content imaging; IB: immunoblot; IF: immunofluorescence; NPC: neuronal precursor cells; MDS: molecular dynamics simulation; PD: Parkinson disease; p-S65-Ub: ubiquitin phosphorylated at Ser65; RMSF: root mean scare fluctuation; TOMM: translocase of outer mitochondrial membrane; TVLN: ubiquitin with T66V and L67N mutation, mimics Ub-CR; Ub: ubiquitin; WT: wild-type.
  •  
12.
  •  
13.
  • Garcia-Moreno, Hector, et al. (författare)
  • Tau and neurofilament light-chain as fluid biomarkers in spinocerebellar ataxia type 3
  • 2022
  • Ingår i: European Journal of Neurology. - : Wiley. - 1351-5101 .- 1468-1331. ; 29:8, s. 2439-2452
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND AND PURPOSE: Clinical trials in spinocerebellar ataxia type 3 (SCA3) will require biomarkers for use as outcome measures.METHODS: To evaluate total tau (t-tau), glial fibrillary acidic protein (GFAP), ubiquitin carboxy-terminal hydrolase L1 (UCHL1) and neurofilament light-chain (NfL) as fluid biomarkers in SCA3, ATXN3 mutation carriers (n = 143) and controls (n = 172) were clinically assessed, and the plasma concentrations of the four proteins were analysed on the Simoa HD-1 platform. Eleven ATXN3 mutation carrier cerebrospinal fluid samples were analysed for t-tau and phosphorylated tau (p-tau181 ). A transgenic SCA3 mouse model (MJDTg) was used to measure cerebellar t-tau levels.RESULTS: Plasma t-tau levels were higher in mutation carriers below the age of 50 compared to controls, and the Inventory of Non-Ataxia Signs was associated with t-tau in ataxic patients (p = 0.004). Pre-ataxic carriers showed higher cerebrospinal fluid t-tau and p-tau181 concentrations compared to ataxic patients (p = 0.025 and p = 0.014, respectively). Cerebellar t-tau was elevated in MJDTg mice compared to wild-type (p = 0.033) only in the early stages of the disease. GFAP and UCHL1 did not show higher levels in mutation carriers compared to controls. Plasma NfL concentrations were higher in mutation carriers compared to controls, and differences were greater for younger carriers. The Scale for the Assessment and Rating of Ataxia was the strongest predictor of NfL in ataxic patients (p < 0.001).CONCLUSION: Our results suggest that tau might be a marker of early disease stages in SCA3. NfL can discriminate mutation carriers from controls and is associated with different clinical variables. Longitudinal studies are required to confirm their potential role as biomarkers in clinical trials.
  •  
14.
  • Gorcenco, Sorina, et al. (författare)
  • Ataxia-pancytopenia syndrome with SAMD9L mutations
  • 2017
  • Ingår i: Neurology: Genetics. - 2376-7839. ; 3:5
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVE: We describe the neurologic, neuroradiologic, and ophthalmologic phenotype of 1 Swedish and 1 Finnish family with autosomal dominant ataxia-pancytopenia (ATXPC) syndrome and SAMD9L mutations.METHODS: Members of these families with germline SAMD9L c.2956C>T, p.Arg986Cys, or c.2672T>C, p.Ile891Thr mutations underwent structured interviews and neurologic and ophthalmologic examinations. Neuroimaging was performed, and medical records were reviewed. Previous publications on SAMD9L-ATXPC were reviewed.RESULTS: Twelve individuals in both families were affected clinically. All mutation carriers examined had balance impairment, although severity was very variable. All but 1 had nystagmus, and all but 1 had pyramidal tract signs. Neurologic features were generally present from childhood on and progressed slowly. Two adult patients, who experienced increasing clumsiness, glare, and difficulties with gaze fixation, had paracentral retinal dysfunction verified by multifocal electroretinography. Brain MRI showed early, marked cerebellar atrophy in most carriers and variable cerebral periventricular white matter T2 hyperintensities. Two children were treated with hematopoietic stem cell transplantation for hematologic malignancies, and the neurologic symptoms of one of these worsened after treatment. Three affected individuals had attention deficit hyperactivity disorder or cognitive problems. Retinal dysfunction was not previously reported in individuals with ATXPC.CONCLUSIONS: The neurologic phenotype of this syndrome is defined by balance or gait impairment, nystagmus, hyperreflexia in the lower limbs and, frequently, marked cerebellar atrophy. Paracentral retinal dysfunction may contribute to glare, reading problems, and clumsiness. Timely diagnosis of ATXPC is important to address the risk for severe hemorrhage, infection, and hematologic malignancies inherent in this syndrome; regular hematologic follow-up might be beneficial.
  •  
15.
  •  
16.
  • Gorcenco, Sorina, et al. (författare)
  • Clinical and genetic analyses of a Swedish patient series diagnosed with ataxia
  • 2024
  • Ingår i: Journal of Neurology. - 0340-5354. ; 271:1, s. 526-542
  • Tidskriftsartikel (refereegranskat)abstract
    • Hereditary ataxia is a heterogeneous group of complex neurological disorders. Next-generation sequencing methods have become a great help in clinical diagnostics, but it may remain challenging to determine if a genetic variant is the cause of the patient’s disease. We compiled a consecutive single-center series of 87 patients from 76 families with progressive ataxia of known or unknown etiology. We investigated them clinically and genetically using whole exome or whole genome sequencing. Test methods were selected depending on family history, clinical phenotype, and availability. Genetic results were interpreted based on the American College of Medical Genetics criteria. For high-suspicion variants of uncertain significance, renewed bioinformatical and clinical evaluation was performed to assess the level of pathogenicity. Thirty (39.5%) of the 76 families had received a genetic diagnosis at the end of our study. We present the predominant etiologies of hereditary ataxia in a Swedish patient series. In two families, we established a clinical diagnosis, although the genetic variant was classified as “of uncertain significance” only, and in an additional three families, results are pending. We found a pathogenic variant in one family, but we suspect that it does not explain the complete clinical picture. We conclude that correctly interpreting genetic variants in complex neurogenetic diseases requires genetics and clinical expertise. The neurologist’s careful phenotyping remains essential to confirm or reject a diagnosis, also by reassessing clinical findings after a candidate genetic variant is suggested. Collaboration between neurology and clinical genetics and combining clinical and research approaches optimizes diagnostic yield.
  •  
17.
  • Gorcenco, Sorina, et al. (författare)
  • New generation genetic testing entering the clinic
  • 2020
  • Ingår i: Parkinsonism and Related Disorders. - : Elsevier BV. - 1353-8020. ; 73, s. 72-84
  • Tidskriftsartikel (refereegranskat)abstract
    • New generation sequencing (NGS) genetic testing is a powerful diagnostic tool and is increasingly used in the clinical workup of patients, especially in unusual presentations or where a positive family history suggests heritable disease. This review addresses the NGS technologies Targeted sequencing (TS), Whole exome sequencing (WES), Whole genome sequencing (WGS), and the use of gene panels or gene lists for clinical diagnostic purposes. These methods primarily assess nucleotide sequence but can also detect copy number variants and many tandem repeat expansions, greatly simplifying diagnostic algorithms for movement disorders. Studies evaluating the efficacy of NGS in diagnosing movement disorders have reported a diagnostic yield of up to 10.1% for familial and 15.7% for early-onset PD, 11.7–37.5% for dystonia, 12.1–61.8% for ataxia/spastic paraplegia and 11.3–28% for combined movement disorders. Patient selection and stringency in the interpretation of the detected variants and genotypes affect diagnostic yield. Careful comparison of the patient's or family's disease features with the previously reported phenotype associated with the same variant or gene can avoid false-positive diagnoses, although some genes are implicated in various phenotypes. Moving from TS to WES and WGS increases the number of patients correctly diagnosed, but for many patients, a genetic cause cannot be identified today. However, new genetically defined entities are discovered at rapid pace, and genetic databases and our knowledge of genotype-phenotype correlations expand steadily. We discuss the need for clear communication of genetic results and suggest a list of aspects to consider when reporting neurogenetic disorders using NGS testing.
  •  
18.
  •  
19.
  • Gorcenco, Sorina, et al. (författare)
  • Patients’ Perspective in Hereditary Ataxia
  • 2022
  • Ingår i: Cerebellum. - : Springer Science and Business Media LLC. - 1473-4222.
  • Tidskriftsartikel (refereegranskat)abstract
    • Hereditary ataxia represents a heterogeneous group of rare disorders with the chronic progression of motor symptoms that often become debilitating. Many forms include additional neurological, cognitive, or other symptoms. Most of these disorders lack specific treatment. We aimed to investigate aspects of patients’ quality of life, experiences, and expectations. Patients with a diagnosis of hereditary ataxia were identified from our center’s diagnostic register, direct referrals, and from a patient organization. We designed a questionnaire with 32 multiple-choice or open-ended questions on disability and impairment of daily life activities, the perceived effect of symptomatic and supportive therapies, coping strategies, and how they used and experienced various sources of information about their neurological disease. We also included the EQ-5D-3L quality-of-life instrument. Results were analyzed statistically for gender, age, and groups with and without a genetic diagnosis, and were compared to published data from the general population. Seventy-five patients returned the questionnaire. Patients reported considerable disease-related disability and impairment and had significantly lower quality-of-life scores than the general population. Physiotherapy and support from family or friends were important for patients’ overall well-being. Patients with a genetic diagnosis had a lower average age at onset and felt more well-informed about their disease than patients without a genetic diagnosis. Patients used internet sources but relied primarily on their doctors to obtain information about their disease. Our study provides insights into hereditary ataxia patients’ experiences that can lead to improvements in medical and nursing care for these patients.
  •  
20.
  • Grover, Sandeep, et al. (författare)
  • Replication of a Novel Parkinson's Locus in a European Ancestry Population
  • 2021
  • Ingår i: Movement Disorders. - : Wiley. - 0885-3185 .- 1531-8257. ; 36:7, s. 1689-1695
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: A recently published East Asian genome-wide association study of Parkinson;s disease (PD) reported 2 novel risk loci, SV2C and WBSCR17.OBJECTIVES: The objective of this study were to determine whether recently reported novel SV2C and WBSCR17 loci contribute to the risk of developing PD in European and East Asian ancestry populations.METHODS: We report an association analysis of recently reported variants with PD in the COURAGE-PD cohort (9673 PD patients; 8465 controls) comprising individuals of European and East Asian ancestries. In addition, publicly available summary data (41,386 PD patients; 476,428 controls) were pooled.RESULTS: Our findings confirmed the role of the SV2C variant in PD pathogenesis (rs246814, COURAGE-PD PEuropean = 6.64 × 10-4 , pooled PD P = 1.15 × 10-11 ). The WBSCR17 rs9638616 was observed as a significant risk marker in the East Asian pooled population only (P = 1.16 × 10-8 ).CONCLUSIONS: Our comprehensive study provides an up-to-date summary of recently detected novel loci in different PD populations and confirmed the role of SV2C locus as a novel risk factor for PD irrespective of the population or ethnic group analyzed. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
  •  
Skapa referenser, mejla, bekava och länka
  • Resultat 11-20 av 99
Typ av publikation
tidskriftsartikel (81)
konferensbidrag (11)
forskningsöversikt (3)
bokkapitel (3)
doktorsavhandling (1)
Typ av innehåll
refereegranskat (92)
övrigt vetenskapligt/konstnärligt (5)
populärvet., debatt m.m. (2)
Författare/redaktör
Puschmann, Andreas (98)
Wszolek, Zbigniew K. (31)
Ross, Owen A. (18)
Nilsson, Christer (13)
Englund, Elisabet (11)
Gorcenco, Sorina (10)
visa fler...
Uitti, Ryan J (10)
Hansson, Oskar (9)
Ilinca, Andreea (9)
Widner, Håkan (8)
Silburn, Peter A. (8)
Mellick, George D. (8)
Aasly, Jan O. (8)
Annesi, Grazia (8)
Jasinska-Myga, Barba ... (8)
Maraganore, Demetriu ... (8)
Kruger, R (7)
Dickson, Dennis W (7)
Wirdefeldt, Karin (7)
Brighina, Laura (7)
Elbaz, Alexis (7)
Brice, Alexis (7)
Wirdefeldt, K (6)
Van Broeckhoven, Chr ... (6)
YGLAND, EMIL (6)
Ioannidis, John P. A ... (6)
Lesage, Suzanne (6)
Brice, A (6)
Lesage, S (6)
Annesi, G (6)
Hattori, N (6)
Toft, M (6)
Kim, YJ (5)
Carr, J. (5)
Sharma, M. (5)
Belin, AC (5)
Nilsson, Karin (5)
Swanberg, Maria (5)
Stefanis, L (5)
Soller, Maria (5)
Rogaeva, E (5)
Mellick, GD (5)
Quattrone, A (5)
Hattori, Nobutaka (5)
Theuns, Jessie (5)
Klein, Christine (5)
Petrucci, S (5)
Brighina, L (5)
Chung, SJ (5)
Farrer, MJ (5)
visa färre...
Lärosäte
Lunds universitet (98)
Karolinska Institutet (16)
Göteborgs universitet (4)
Uppsala universitet (2)
Linköpings universitet (2)
Umeå universitet (1)
visa fler...
Örebro universitet (1)
visa färre...
Språk
Engelska (98)
Svenska (1)
Forskningsämne (UKÄ/SCB)
Medicin och hälsovetenskap (97)
Naturvetenskap (2)

År

Kungliga biblioteket hanterar dina personuppgifter i enlighet med EU:s dataskyddsförordning (2018), GDPR. Läs mer om hur det funkar här.
Så här hanterar KB dina uppgifter vid användning av denna tjänst.

 
pil uppåt Stäng

Kopiera och spara länken för att återkomma till aktuell vy