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- van der Lee, S. J., et al.
(författare)
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A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer's disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity
- 2019
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Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 138:2, s. 237-250
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Tidskriftsartikel (refereegranskat)abstract
- The genetic variant rs72824905-G (minor allele) in the PLCG2 gene was previously associated with a reduced Alzheimer's disease risk (AD). The role of PLCG2 in immune system signaling suggests it may also protect against other neurodegenerative diseases and possibly associates with longevity. We studied the effect of the rs72824905-G on seven neurodegenerative diseases and longevity, using 53,627 patients, 3,516 long-lived individuals and 149,290 study-matched controls. We replicated the association of rs72824905-G with reduced AD risk and we found an association with reduced risk of dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD). We did not find evidence for an effect on Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) risks, despite adequate sample sizes. Conversely, the rs72824905-G allele was associated with increased likelihood of longevity. By-proxy analyses in the UK Biobank supported the associations with both dementia and longevity. Concluding, rs72824905-G has a protective effect against multiple neurodegenerative diseases indicating shared aspects of disease etiology. Our findings merit studying the PLC gamma 2 pathway as drug-target.
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| 3. |
- Springer, W, et al.
(författare)
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Heterozygous PINK1 p.G411S mutation increases risk for Parkinson's disease (PD)
- 2016
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Ingår i: Movement Disorders. - : Wiley. - 0885-3185. ; 31:Suppl. S2, s. 282-282
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Konferensbidrag (refereegranskat)abstract
- Objective: To investigate the possible disease-association and pathogenic mechanisms of heterozygous PINK1 mutations from a genetic, functional, and structural perspective. Background: It has been postulated that heterozygous mutations in recessive PD genes may increase disease risk. In particular, the PINK1 p.G411S mutation has been reported in families with dominant inheritance patterns, suggesting that it might confer a sizeable disease risk. Methods: We performed a pedigree analysis of seven patients with a heterozygous PINK1 p.G411S mutation with at least one additional affected family member. We screened five case-control series and performed a meta-analysis of previous studies that had examined the variant. For functional cell-based analyses, we used patients skin fibroblast from PINK1 p.G411S or p.Q456X heterozygotes and investigated endogenous protein levels and kinase activity by biochemistry and imaging. For structural analyses, we performed molecular modeling and generated monomeric and dimeric forms of wild type (WT) and mutant PINK1 protein. Using molecular dynamics simulations, we analyzed effects of the p.G411S mutation on WT PINK1 in a heterodimeric complex over time. Results: Our analyses revealed a genetic association of heterozygous PINK1 p.G411S mutation with an increased risk for PD and a possible dominant inheritance with incomplete co-segregation. In patients skin fibroblasts, we establish a dominant negative mode for heterozygous p.G411S mutations under endogenous conditions. While total PINK1 protein levels were similar to controls upon mitochondrial stress, cellular PINK1 kinase activity was significantly reduced in p.G411S heterozygotes compared to WT and importantly to p.Q456X heterozygotes, which resulted in 50% reduction of PINK1 protein levels. Structural analyses supported our hypothesis that the p.G411S mutation can poison PINK1 WT in a heterodimeric complex and thus effectively reduce cellular PINK1 kinase activity. This in turn impairs the protective functions of the PINK1/PARKIN-mediated mitochondrial quality control. Conclusions: Our study uncovers increased disease risk and molecular mechanisms of a particular heterozygous mutation in a recessive PD gene. Based on genetic and clinical evaluation as well as functional and structural characterization, we established PINK1 p.G411S as a rare genetic risk factor with a relatively large effect size conferred by a dominant negative function phenotype.
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| 4. |
- Sundal, Christina, et al.
(författare)
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Hereditary diffuse leukoencephalopathy with spheroids with phenotype of primary progressive multiple sclerosis
- 2015
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Ingår i: European Journal of Neurology. - : Wiley. - 1351-5101 .- 1468-1331. ; 22:2, s. 328-333
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Tidskriftsartikel (refereegranskat)abstract
- Background and purpose Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is a devastating, hereditary white matter (WM) disorder with heterogeneous neuropsychiatric features. Colony stimulating factor 1 receptor (CSF1R) mutations were looked for in primary progressive multiple sclerosis (PPMS) patients and the clinical features of a family with a novel CSF1R mutation are reported. Methods CSF1R exons 12−22 in a cohort of 220 PPMS patients from the Swedish and Norwegian national multiple sclerosis registries were sequenced. Results One patient had a novel mutation, c.2562T>A; p.Asn854Lys, in the CSF1R gene. Her symptoms started at the age of 29 years with insidious onset of pyramidal weakness in the left leg. The cerebrospinal fluid examination showed four intrathecal immunoglobulin G bands. A magnetic resonance imaging scan performed 4 years after symptom onset demonstrated patchy deep WM lesions. She was diagnosed as having PPMS and treated with intramuscular interferon beta 1a. Due to slow disease progression, the development of memory decline and cerebellar signs, she was given subcutaneous interferon beta 1a without any benefit. The updated pedigree indicated that five siblings also had the CSF1R gene mutation; one was diagnosed with PPMS. Six more distant relatives also had a neurological disorder; four were clinically diagnosed with PPMS. Conclusions Our study indicates that a chronic course of HDLS may mimic PPMS. Genetic testing for CSF1R gene mutations in PPMS cases with a positive family history of neurological disorders may establish the diagnosis of HDLS.
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| 5. |
- Perez-Soriano, Alexandra, et al.
(författare)
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PBB3 Imaging in Parkinsonian disorders: Evidence for binding to abnormally aggregated proteins in addition to tau proteins
- 2017
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Ingår i: Movement Disorders. - : Wiley. - 1531-8257 .- 0885-3185. ; 32:Suppl 2, s. 585-587
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Konferensbidrag (refereegranskat)abstract
- Objective: To study selective regional binding for tau pathology in vivo, using PET with [11C]PBB3 ([11C]methylamino pyridin-3-yl buta-1,3-dienyl benzo[d]thiazol-6-ol) in tauopathies, and in conditions not typically associated with tauopathy. Background: Tau imaging is a promising tool to study the link between tau and neurodegeneration. The specificity of tracers in vivo however remains uncertain, and off target binding is frequently present, limiting its use in parkinsonian disorders. Methods: Dynamic PET scans were obtained for 70 min after the bolus injection of [11C]PBB3 (mean dose 518.97MBq) in five PSP subjects, 1 subject with DCTN1 mutation and PSP phenotype,3 asymptomatic SNCA duplication carriers, 1 MSA subject, and 7 healthy controls of similar age. The occipital cortex was used as reference region for the PSP , the DCTN1 mutation and the MSA subjects. The cerebellar white matter was used as a reference region for the SNCA duplication carriers. Tissue reference Logan analysis was applied to each region of interest (ROI) using the appropriate reference region. Results: In PSP subjects, the highest retention of [11C]PBB3 was observed in putamen, midbrain, globus pallidus and substantia nigra. Longer disease duration and more advanced clinical severity were generally associated with higher tracer retention. The DCTN1/PSP phenotype case showed increased binding in putamen, parietal lobe, and globus pallidus. In SNCA duplication carriers there was a significant increase of [11C] PBB3 binding compared to controls in globus pallidus, putamen, thalamus, ventral striatum, substantia nigra, and pedunculopontine nucleus. The MSA case showed increased binding in comparison to the control group in frontal lobe, globus pallidus, midbrain, parietal lobe, putamen, temporal lobe, substantia nigra, thalamus and ventral striatum. Conclusions: All PSP patients showed increased retention of the tracer in the basal ganglia, as clinically expected. However, binding was also present in asymptomatic SNCA duplication carriers as well as the subject with MSA, which are not typically associated with pathological tau deposition. This suggests the possibility that [11C]PBB3 binds to alpha-synuclein or other proteins involved in neurodegeneration.
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