References of "Annals of Neurology"
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See detailMtDNA deletions discriminate affected from unaffected LRRK2 mutation carriers
Ouzren, Nassima UL; Delcambre, Sylvie UL; Ghelfi, Jenny UL et al

in Annals of Neurology (2019), 86(2), 324-326

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See detailUsing global team science to identify genetic parkinson's disease worldwide
Krüger, Rejko UL; Vollstedt, Eva‐Juliane; Kasten, Meike et al

in Annals of Neurology (2019)

Large multicenter approaches are necessary to systematically and uniformly characterize patients with genetic neurologic conditions and to eventually establish sizable clinical trial-ready cohorts.

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See detailSubcellular origin of mitochondrial DNA deletions in human skeletal muscle.
Vincent, Amy E; Rosa, Hannah S; Pabis, Kamil et al

in Annals of Neurology (2018), 84(2), 289-301

OBJECTIVE: In patients with mitochondrial DNA (mtDNA) maintenance disorders and with aging, mtDNA deletions sporadically form and clonally expand within individual muscle fibers, causing respiratory chain ... [more ▼]

OBJECTIVE: In patients with mitochondrial DNA (mtDNA) maintenance disorders and with aging, mtDNA deletions sporadically form and clonally expand within individual muscle fibers, causing respiratory chain deficiency. This study aimed to identify the sub-cellular origin and potential mechanisms underlying this process. METHODS: Serial skeletal muscle cryosections from patients with multiple mtDNA deletions were subjected to subcellular immunofluorescent, histochemical, and genetic analysis. RESULTS: We report respiratory chain-deficient perinuclear foci containing mtDNA deletions, which show local elevations of both mitochondrial mass and mtDNA copy number. These subcellular foci of respiratory chain deficiency are associated with a local increase in mitochondrial biogenesis and unfolded protein response signaling pathways. We also find that the commonly reported segmental pattern of mitochondrial deficiency is consistent with the three-dimensional organization of the human skeletal muscle mitochondrial network. INTERPRETATION: We propose that mtDNA deletions first exceed the biochemical threshold causing biochemical deficiency in focal regions adjacent to the myonuclei, and induce mitochondrial biogenesis before spreading across the muscle fiber. These subcellular resolution data provide new insights into the possible origin of mitochondrial respiratory chain deficiency in mitochondrial myopathy. [less ▲]

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See detailInvolvement of the cerebellum in Parkinson disease and dementia with Lewy bodies.
Seidel, Kay; Bouzrou, Mohamed; Heidemann, Nina et al

in Annals of neurology (2017), 81(6), 898-903

Brains from patients with Parkinson disease or dementia with Lewy bodies show aggregation of alpha-synuclein in precerebellar brainstem structures. Furthermore, patients exhibit resting tremor, unstable ... [more ▼]

Brains from patients with Parkinson disease or dementia with Lewy bodies show aggregation of alpha-synuclein in precerebellar brainstem structures. Furthermore, patients exhibit resting tremor, unstable gait, and impaired balance, which may be associated with cerebellar dysfunction. Therefore, we screened the cerebella of 12 patients with alpha-synucleinopathies for neuropathological changes. Cerebellar nuclei and neighboring white matter displayed numerous aggregates, whereas lobules were mildly affected. Cerebellar aggregation pathology may suggest a prionlike spread originating from affected precerebellar structures, and the high homogeneity between patients with dementia with Lewy bodies and Parkinson disease shows that both diseases likely belong to the same neuropathological spectrum. Ann Neurol 2017;81:898-903. [less ▲]

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See detailLeigh Map: A Novel Computational Diagnostic Resource for Mitochondrial Disease
Rhaman, Joyeeta; Noronha, Alberto UL; Thiele, Ines UL et al

in Annals of Neurology (2017)

Mitochondrial disorders are amongst the most severe metabolic disorders and are beset by genetic, biochemical, and clinical heterogeneity. Variation between individuals and poor understanding of disease ... [more ▼]

Mitochondrial disorders are amongst the most severe metabolic disorders and are beset by genetic, biochemical, and clinical heterogeneity. Variation between individuals and poor understanding of disease pathophysiology pose significant diagnostic challenges. We present a novel interactive computational network, the Leigh Map, cataloguing >1700 gene-to-phenotype interactions in Leigh syndrome, the most common and genetically heterogeneous mitochondrial disorder. Blinded validation of the Leigh Map yielded an 80% success rate in correct identification of causative genes. We conclude that the Leigh Map is an efficacious resource that, in combination with whole-exome sequencing, can be utilized as a novel diagnostic resource for mitochondrial disease. [less ▲]

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See detailMitochondrial DNA depletion in respiratory chain-deficient Parkinson disease neurons.
Grünewald, Anne UL; Rygiel, Karolina A.; Hepplewhite, Philippa D. et al

in Annals of Neurology (2016), 79(3), 366-378

OBJECTIVE: To determine the extent of respiratory chain abnormalities and investigate the contribution of mitochondrial DNA (mtDNA) to the loss of respiratory chain complexes (CI-IV) in the substantia ... [more ▼]

OBJECTIVE: To determine the extent of respiratory chain abnormalities and investigate the contribution of mitochondrial DNA (mtDNA) to the loss of respiratory chain complexes (CI-IV) in the substantia nigra (SN) of idiopathic Parkinson disease (IPD) patients at the single-neuron level. METHODS: Multiple-label immunofluorescence was applied to postmortem sections of 10 IPD patients and 10 controls to quantify the abundance of CI-IV subunits (NDUFB8 or NDUFA13, SDHA, UQCRC2 and COXI), and mitochondrial transcription factors (TFAM and TFB2M) relative to mitochondrial mass (Porin and GRP75) in dopaminergic neurons. To assess the involvement of mtDNA in respiratory chain deficiency in IPD, SN neurons, isolated with laser-capture microdissection, were assayed for mtDNA deletions, copy number and presence of transcription/replication-associated 7S DNA employing a triplex real-time PCR assay. RESULTS: While mitochondrial mass was unchanged in single SN neurons from IPD patients, we observed a significant reduction in the abundances of CI and II subunits. At single-cell level, CI and II deficiencies were correlated in patients. The CI deficit concomitantly occurred with low abundances of the mtDNA transcription factors TFAM and TFB2M, which also initiate transcription-primed mtDNA replication. Consistent with this, real-time PCR analysis revealed fewer transcription/replication-associated mtDNA molecules and an overall reduction in mtDNA copy number in patients. This effect was more pronounced in single IPD neurons with severe complex I deficiency. INTERPRETATION: Respiratory chain dysfunction in IPD neurons not only involves CI, but also extends to CII. These deficiencies are possibly a consequence of the interplay between nDNA and mtDNA-encoded factors mechanistically connected via TFAM. This article is protected by copyright. All rights reserved. [less ▲]

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See detailIndependent and joint effects of the MAPT and SNCA genes in Parkinson disease.
Elbaz, Alexis; Ross, Owen A.; Ioannidis, John P. A. et al

in Annals of neurology (2011), 69(5), 778-92

OBJECTIVE: We studied the independent and joint effects of the genes encoding alpha-synuclein (SNCA) and microtubule-associated protein tau (MAPT) in Parkinson disease (PD) as part of a large meta ... [more ▼]

OBJECTIVE: We studied the independent and joint effects of the genes encoding alpha-synuclein (SNCA) and microtubule-associated protein tau (MAPT) in Parkinson disease (PD) as part of a large meta-analysis of individual data from case-control studies participating in the Genetic Epidemiology of Parkinson's Disease (GEO-PD) consortium. METHODS: Participants of Caucasian ancestry were genotyped for a total of 4 SNCA (rs2583988, rs181489, rs356219, rs11931074) and 2 MAPT (rs1052553, rs242557) single nucleotide polymorphism (SNPs). Individual and joint effects of SNCA and MAPT SNPs were investigated using fixed- and random-effects logistic regression models. Interactions were studied on both a multiplicative and an additive scale, and using a case-control and case-only approach. RESULTS: Fifteen GEO-PD sites contributed a total of 5,302 cases and 4,161 controls. All 4 SNCA SNPs and the MAPT H1-haplotype-defining SNP (rs1052553) displayed a highly significant marginal association with PD at the significance level adjusted for multiple comparisons. For SNCA, the strongest associations were observed for SNPs located at the 3' end of the gene. There was no evidence of statistical interaction between any of the 4 SNCA SNPs and rs1052553 or rs242557, neither on the multiplicative nor on the additive scale. INTERPRETATION: This study confirms the association between PD and both SNCA SNPs and the H1 MAPT haplotype. It shows, based on a variety of approaches, that the joint action of variants in these 2 loci is consistent with independent effects of the genes without additional interacting effects. [less ▲]

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See detailFirst appraisal of brain pathology owing to A30P mutant alpha-synuclein.
Seidel, Kay; Schols, Ludger; Nuber, Silke et al

in Annals of neurology (2010), 67(5), 684-9

Familial Parkinson disease (PD) due to the A30P mutation in the SNCA gene encoding alpha-synuclein is clinically associated with PD symptoms. In this first pathoanatomical study of the brain of an A30P ... [more ▼]

Familial Parkinson disease (PD) due to the A30P mutation in the SNCA gene encoding alpha-synuclein is clinically associated with PD symptoms. In this first pathoanatomical study of the brain of an A30P mutation carrier, we observed neuronal loss in the substantia nigra, locus coeruleus, and dorsal motor vagal nucleus, as well as widespread occurrence of alpha-synuclein immunopositive Lewy bodies, Lewy neurites, and glial aggregates. Alpha-synuclein aggregates ultrastructurally resembled Lewy bodies, and biochemical analyses disclosed a significant load of insoluble alpha-synuclein, indicating neuropathological similarities between A30P disease patients and idiopathic PD, with a more severe neuropathology in A30P carriers. [less ▲]

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See detailSingle-cell expression profiling of dopaminergic neurons combined with association analysis identifies pyridoxal kinase as Parkinson's disease gene.
Elstner, Matthias; Morris, Christopher M.; Heim, Katharina et al

in Annals of neurology (2009), 66(6), 792-8

OBJECTIVE: The etiology of Parkinson disease (PD) is complex and multifactorial, with hereditary and environmental factors contributing. Monogenic forms have provided molecular clues to disease mechanisms ... [more ▼]

OBJECTIVE: The etiology of Parkinson disease (PD) is complex and multifactorial, with hereditary and environmental factors contributing. Monogenic forms have provided molecular clues to disease mechanisms but genetic modifiers of idiopathic PD are still to be determined. METHODS: We carried out whole-genome expression profiling of isolated human substantia nigra (SN) neurons from patients with PD vs. controls followed by association analysis of tagging single-nucleotide polymorphisms (SNPs) in differentially regulated genes. Association was investigated in a German PD sample and confirmed in Italian and British cohorts. RESULTS: We identified four differentially expressed genes located in PD candidate pathways, ie, MTND2 (mitochondrial, p = 7.14 x 10(-7)), PDXK (vitamin B6/dopamine metabolism, p = 3.27 x 10(-6)), SRGAP3 (axon guidance, p = 5.65 x 10(-6)), and TRAPPC4 (vesicle transport, p = 5.81 x 10(-6)). We identified a DNA variant (rs2010795) in PDXK associated with an increased risk of PD in the German cohort (p = 0.00032). This association was confirmed in the British (p = 0.028) and Italian (p = 0.0025) cohorts individually and reached a combined value of p = 1.2 x 10(-7) (odds ratio [OR], 1.3; 95% confidence interval [CI], 1.18-1.44). INTERPRETATION: We provide an example of how microgenomic genome-wide expression studies in combination with association analysis can aid to identify genetic modifiers in neurodegenerative disorders. The detection of a genetic variant in PDXK, together with evidence accumulating from clinical studies, emphasize the impact of vitamin B6 status and metabolism on disease risk and therapy in PD. [less ▲]

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See detailUCHL1 is a Parkinson's disease susceptibility gene.
Maraganore, Demetrius M.; Lesnick, Timothy G.; Elbaz, Alexis et al

in Annals of neurology (2004), 55(4), 512-21

The reported inverse association between the S18Y variant of the ubiquitin carboxy-terminal hydrolase L1 (UCHL1) gene and Parkinson's disease (PD) has strong biological plausibility. If confirmed, genetic ... [more ▼]

The reported inverse association between the S18Y variant of the ubiquitin carboxy-terminal hydrolase L1 (UCHL1) gene and Parkinson's disease (PD) has strong biological plausibility. If confirmed, genetic association of this variant with PD may support molecular targeting of the UCHL1 gene and its product as a therapeutic strategy for PD. In this light, we performed a collaborative pooled analysis of individual-level data from all 11 published studies of the UCHL1 S18Y gene variant and PD. There were 1,970 cases and 2,224 unrelated controls. We found a statistically significant inverse association of S18Y with PD. Carriers of the variant allele (Y/Y plus Y/S vs S/S) had an odds ratio (OR) of 0.84 (95% confidence interval [CI], 0.73-0.95) and homozygotes for the variant allele (Y/Y vs S/S plus Y/S) had an OR of 0.71 (95% CI, 0.57-0.88). There was a linear trend in the log OR consistent with a gene dose effect (p = 0.01). The inverse association was most apparent for young cases compared with young controls. There was no evidence for publication bias and the associations remained significant after excluding the first published, hypothesis-generating study. These findings confirm that UCHL1 is a susceptibility gene for PD and a potential target for disease-modifying therapies. [less ▲]

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See detailIncreased susceptibility to sporadic Parkinson's disease by a certain combined alpha-synuclein/apolipoprotein E genotype.
Krüger, Rejko UL; Vieira-Saecker, A. M.; Kuhn, W. et al

in Annals of neurology (1999), 45(5), 611-7

Parkinson's disease (PD) is one of the most common neurodegenerative disorders affecting about 1% of Western populations older than age 50. The pathological hallmark of PD are Lewy bodies, that is ... [more ▼]

Parkinson's disease (PD) is one of the most common neurodegenerative disorders affecting about 1% of Western populations older than age 50. The pathological hallmark of PD are Lewy bodies, that is, intracytoplasmic inclusion bodies in affected neurons of the substantia nigra. Recently, alpha-synuclein (alpha-SYN) has been identified as the main component of Lewy bodies in sporadic PD, suggesting involvement in neurodegeneration via protein accumulation. The partially overlapping pathology of PD and Alzheimer's disease, as well as striking structural similarities of alpha-SYN and apolipoprotein E, which is a major risk factor for late-onset Alzheimer's disease, prompted us to investigate the influence of different alpha-SYN and apolipoprotein E alleles for developing sporadic PD. We performed association studies in 193 German PD patients and 200 healthy control subjects matched for age, sex, and origin. A polymorphism in the promoter region of the alpha-SYN gene (NACP-Rep1) as well as of the closely linked DNA markers D4S1647 and D4S1628 revealed significant differences in the allelic distributions between PD patients and the control group. Furthermore, the Apo epsilon4 allele but not the Th1/E47 promoter polymorphism of the apolipoprotein E gene was significantly more frequent among early-onset PD patients (age at onset, <50 years) than in late-onset PD. Regarding the combination of the Apo epsilon4 allele and allele 1 of the alpha-SYN promoter polymorphism, a highly significant difference between the group of PD patients and control individuals has been found, suggesting interactions or combined actions of these proteins in the pathogenesis of sporadic PD. PD patients harboring this genotype have a 12.8-fold increased relative risk for developing PD during their lives. [less ▲]

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