Assessing the relationship between monoallelic PRKN mutations and Parkinson's risk.
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ABSTRACT:
SUBMITTER: Lubbe SJ
PROVIDER: S-EPMC8033143 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:PRKN mutations are the most common recessive cause of Parkinson's disease and are a promising target for gene and cell replacement therapies. Identification of biallelic PRKN patients at the population scale, however, remains a challenge, as roughly half are copy number variants and many single nucleotide polymorphisms are of unclear significance. Additionally, the true prevalence and disease risk associated with heterozygous PRKN mutations is unclear, as a comprehensive assessment of PRKN mutations has not been performed at a population scale. To address these challenges, we evaluated PRKN mutations in two cohorts with near complete genotyping of both single nucleotide polymorphisms and copy number variants: the NIH-PD + AMP-PD cohort, the largest Parkinson's disease case-control cohort with whole genome sequencing data from 4094 participants, and the UK Biobank, the largest cohort study with whole exome sequencing and genotyping array data from 200 606 participants. Using the NIH-PD participants, who were genotyped using whole genome sequencing, genotyping array, and multi-plex ligation-dependent probe amplification, we validated genotyping array for the detection of copy number variants. Additionally, in the NIH-PD cohort, functional assays of patient fibroblasts resolved variants of unclear significance in biallelic carriers and suggested that cryptic loss of function variants in monoallelic carriers are not a substantial confounder for association studies. In the UK Biobank, we identified 2692 PRKN copy number variants from genotyping array data from nearly half a million participants (the largest collection to date). Deletions or duplications involving exon 2 accounted for roughly half of all copy number variants and the vast majority (88%) involved exons 2, 3, or 4. In the UK Biobank, we found a pathogenic PRKN mutation in 1.8% of participants and two mutations in ∼1/7800 participants. Those with one PRKN pathogenic variant were as likely as non-carriers to have Parkinson's disease [odds ratio = 0.91 (0.58-1.38), P-value 0.76] or a parent with Parkinson's disease [odds ratio = 1.12 (0.94-1.31), P-value = 0.19]. Similarly, those in the NIH-PD + AMP + PD cohort with one PRKN pathogenic variant were as likely as non-carriers to have Parkinson's disease [odds ratio = 1.29 (0.74-2.38), P-value = 0.43]. Together our results demonstrate that heterozygous pathogenic PRKN mutations are common in the population but do not increase the risk of Parkinson's disease.
| S-EPMC9423714 | biostudies-literature
Project description:Bi-allelic pathogenic variants in PRKN are the most common cause of autosomal recessive Parkinson's disease (PD). 647 patients with PRKN-PD were included in this international study. The pathogenic variants present were characterised and investigated for their effect on phenotype. Clinical features and progression of PRKN-PD was also assessed. Among 133 variants in index cases (n = 582), there were 58 (43.6%) structural variants, 34 (25.6%) missense, 20 (15%) frameshift, 10 splice site (7.5%%), 9 (6.8%) nonsense and 2 (1.5%) indels. The most frequent variant overall was an exon 3 deletion (n = 145, 12.3%), followed by the p.R275W substitution (n = 117, 10%). Exon3, RING0 protein domain and the ubiquitin-like protein domain were mutational hotspots with 31%, 35.4% and 31.7% of index cases presenting mutations in these regions respectively. The presence of a frameshift or structural variant was associated with a 3.4 ± 1.6 years or a 4.7 ± 1.6 years earlier age at onset of PRKN-PD respectively (p < 0.05). Furthermore, variants located in the N-terminus of the protein, a region enriched with frameshift variants, were associated with an earlier age at onset. The phenotype of PRKN-PD was characterised by slow motor progression, preserved cognition, an excellent motor response to levodopa therapy and later development of motor complications compared to early-onset PD. Non-motor symptoms were however common in PRKN-PD. Our findings on the relationship between the type of variant in PRKN and the phenotype of the disease may have implications for both genetic counselling and the design of precision clinical trials.
| S-EPMC10980707 | biostudies-literature
Project description:ObjectiveTo assess whether dietary fat intake influences Parkinson's disease risk.Data sourcesWe systematically surveyed the Embase and PubMed databases, reviewing manuscripts published prior to October 2018. The following terms were used: ("Paralysis agitans" OR "Parkinson disease" OR "Parkinson" OR "Parkinson's" OR "Parkinson's disease") AND ("fat" OR "dietary fat" OR "dietary fat intake").Data selectionIncluded studies were those with both dietary fat intake and Parkinson's disease risk as exposure factors. The Newcastle-Ottawa Scale was adapted to investigate the quality of included studies. Stata V12.0 software was used for statistical analysis.Outcome measuresThe primary outcomes included the relationship between high total energy intake, high total fat intake, and Parkinson's disease risk. The secondary outcomes included the relationship between different kinds of fatty acids and Parkinson's disease risk.ResultsNine articles met the inclusion criteria and were incorporated into this meta-analysis. Four studies scored 7 and the other five studies scored 9 on the Newcastle-Ottawa Scale, meaning that all studies were of high quality. Meta-analysis results showed that high total energy intake was associated with an increased risk of Parkinson's disease (P = 0.000, odds ratio (OR) = 1.49, 95% confidence interval (CI): 1.26-1.75); in contrast, high total fat intake was not associated with Parkinson's disease risk (P = 0.123, OR = 1.07, 95% CI: 0.91-1.25). Subgroup analysis revealed that polyunsaturated fatty acid intake (P = 0.010, OR = 1.03, 95% CI: 0.88-1.20) reduced the risk of Parkinson's disease, while arachidonic acid (P = 0.026, OR = 1.15, 95% CI: 0.97-1.37) and cholesterol (P = 0.002, OR = 1.09, 95% CI: 0.92-1.29) both increased the risk of Parkinson's disease. Subgroup analysis also demonstrated that, although the results were not significant, consumption of n-3 polyunsaturated fatty acids (P = 0.071, OR = 0.88, 95% CI: 0.73-1.05), ?-linolenic acid (P = 0.06, OR = 0.86, 95% CI: 0.72-1.02), and the n-3 to n-6 ratio (P = 0.458, OR = 0.89, 95% CI: 0.75-1.06) were all linked with a trend toward reduced Parkinson's disease risk. Monounsaturated fatty acid (P = 0.450, OR = 1.06, 95% CI: 0.91-1.23), n-6 polyunsaturated fatty acids (P = 0.100, OR = 1.15, 95% CI: 0.96-1.36) and linoleic acid (P = 0.053, OR = 1.11, 95% CI: 0.94-1.32) intakes were associated with a non-significant trend toward higher PD risk. Saturated fatty acid (P = 0.619, OR = 1.01, 95% CI: 0.87-1.18) intake was not associated with Parkinson's disease.ConclusionDietary fat intake affects Parkinson's disease risk, although this depends on the fatty acid subtype. Higher intake of polyunsaturated fatty acids may reduce the risk of Parkinson's disease, while higher cholesterol and arachidonic acid intakes may elevate Parkinson's disease risk. However, further studies and evidence are needed to validate any link between dietary fat intake and Parkinson's disease.
| S-EPMC6788237 | biostudies-literature
Project description:Parkin (PRKN) mutations are a common cause of early-onset parkinsonism, however the role of this gene in typical late-onset Parkinson's disease (PD) remains unresolved. A single nucleotide polymorphism in the promoter region (PRKN-258; rs9347683) has been observed to associate with PD, affect age-at-onset (AAO) of symptoms, and to functionally effect differential expression of the PRKN transcript. In the present study, PRKN-258 did not associate with PD, and no evidence for an AAO effect was observed in three age and gender-matched Caucasian patient-control series from Norway, Ireland and the US. These data do not support a role for this common variant in PD etiology.
| S-EPMC4381345 | biostudies-literature
Project description:Germline mutations in the DNA base excision repair gene MUTYH are known to increase a carrier's risk of colorectal cancer. However, the risks of other (extracolonic) cancers for MUTYH mutation carriers are not well defined. We identified 266 probands (91% Caucasians) with a MUTYH mutation (41 biallelic and 225 monoallelic) from the Colon Cancer Family Registry. Mutation status, sex, age and histories of cancer from their 1,903 first- and 3,255 second-degree relatives were analyzed using modified segregation analysis conditioned on the ascertainment criteria. Compared with incidences for the general population, hazard ratios (HRs) (95% confidence intervals [CIs]) for biallelic MUTYH mutation carriers were: urinary bladder cancer 19 (3.7-97) and ovarian cancer 17 (2.4-115). The HRs (95% CI) for monoallelic MUTYH mutation carriers were: gastric cancer 9.3 (6.7-13); hepatobiliary cancer 4.5 (2.7-7.5); endometrial cancer 2.1 (1.1-3.9) and breast cancer 1.4 (1.0-2.0). There was no evidence for an increased risk of cancers at the other sites examined (brain, pancreas, kidney or prostate). Based on the USA population incidences, the estimated cumulative risks (95% CI) to age 70 years for biallelic mutation carriers were: bladder cancer 25% (5-77%) for males and 8% (2-33%) for females and ovarian cancer 14% (2-65%). The cumulative risks (95% CI) for monoallelic mutation carriers were: gastric cancer 5% (4-7%) for males and 2.3% (1.7-3.3%) for females; hepatobiliary cancer 3% (2-5%) for males and 1.4% (0.8-2.3%) for females; endometrial cancer 3% (2%-6%) and breast cancer 11% (8-16%). These unbiased estimates of both relative and absolute risks of extracolonic cancers for people, mostly Caucasians, with MUTYH mutations will be important for their clinical management.
| S-EPMC5094810 | biostudies-literature
Project description: Not available
| S-EPMC6379106 | biostudies-literature
Project description:Parkinson's disease (PD) is featured with motor disorder and nonmotor manifestations including psychological symptoms, autonomic nervous system dysfunction, and paresthesia, which results in great inconvenience to the patients' life. The apolipoprotein (Apo) superfamily, as a group of potentially modifiable biomarkers in clinical practice, is of increasing significance in the diagnosis, evaluation, and prognosis of PD. The present review summarized the current understanding and emerging findings of the relationship between Apo superfamily and PD.All literatures were identified by systematically searching PubMed, Embase, and Cochrane electronic databases with terms "Parkinson disease," "apolipoprotein," and their synonyms until May 2017.We have thoroughly examined titles and abstracts of all the literatures that met our search strategy and the full text if the research is identified or not so definite. Reference lists of retrieved articles were also scrutinized for additional relevant studies.The levels of plasma ApoA1 are inversely correlated with the risk of PD and the lower levels of ApoA1 trend toward association with poorer motor performance. Higher ApoD expression in neurons represents more puissant protection against PD, which is critical in delaying the neurodegeneration process of PD. It is suggested that APOE alleles are related to development and progression of cognitive decline and age of PD onset, but conclusions are not completely identical, which may be attributed to different ApoE isoforms. APOJ gene expressions are upregulated in PD patients and it is possible that high ApoJ level is an indicator of PD dementia and correlates with specific phenotypic variations in PD.The Apo superfamily has been proved to be closely involved in the initiation, progression, and prognosis of PD. Apos and their genes are of great value in predicting the susceptibility of PD and hopeful to become the target of medical intervention to prevent the onset of PD or slow down the progress. Therefore, further large-scale studies are warranted to elucidate the precise mechanisms of Apos in PD.
| S-EPMC5678263 | biostudies-literature
Project description:Mutations in the E3 ubiquitin ligase Parkin cause autosomal recessive Parkinson’s disease. In concert with PINK1, Parkin regulates the clearance of dysfunctional mitochondria via lysosomes. In response, new mitochondria are generated through an interplay of nuclear- and mitochondrial-encoded proteins. Mouse and overexpression models suggests that Parkin also influences these processes, both in the nuclear cascade and at the level of the mitochondrial genome. Additionally, Parkin has been shown to prevent mitochondrial membrane permeation, impeding the escape of mitochondrial DNA (mtDNA). In line with this, serum from Parkin mutation carriers showed higher levels of circulating cell-free mtDNA (ccf-mtDNA) and inflammatory cytokines – a result of the innate immune response - which can be triggered by cytosolic mtDNA. However, Parkin’s relationship with the mitochondrial genome and the mitogenesis pathway has not been explored in patient-derived neurons. To investigate this aspect of Parkin’s cellular function endogenously, we generated induced pluripotent stem cell (iPSC)-derived midbrain neurons from Parkin mutation carriers and healthy controls. In Parkin-deficient cells, several factors in the mitochondrial biogenesis pathway were significantly reduced, resulting in impaired mtDNA homeostasis - a phenomenon that was exacerbated in dopaminergic neurons. Moreover, in response to a lack of freely accessible NAD+, the energy sensor Sirtuin 1, which simultaneously controls mtDNA maintenance processes and mitophagy, was downregulated in Parkin-deficient neurons. However, while impaired lysosomal degradation of mitochondria was only detectable in oxidative conditions, biogenesis defects were already apparent in untreated patient neurons. This may suggest that mitophagy disruption occurs in response to acute stress. By contrast, the biogenesis pathway may be continually impaired in Parkin-associated Parkinson’s disease. Next, using a mutagenic stress model in combination with Parkin knockdown, we detected an increase in ccf-mtDNA and the cytosolic DNA sensor cGAS. To explore if ccf-mtDNA can act as damage-associated molecular pattern in the brain, we used postmortem tissue from a Parkin mutation carrier and performed single-cell RNA sequencing. In the midbrain lacking Parkin, we found a higher percentage of microglia along with an upregulation of proinflammatory cytokines in these cells. Together, our findings suggest a role for Parkin in the control of mitochondrial biogenesis and mtDNA maintenance, which protects midbrain neurons from neuroinflammation-induced degeneration. Future research in iPSC-derived neuron-microglia co-culture systems could aim at developing PD treatment approaches that target the neuronal release or microglial uptake of ccf-mtDNA.
2021-03-05 | GSE166790 | GEO
Project description:Visuocortical activity and pupil diameter both increase in tasks involving memory, attention, and physiological arousal. Thus, the question arises whether pupil dilation prompts a subsequent increase in visuocortical activity. In this study, we investigated the extent to which changes in visuocortical activity relate to changes in pupil diameter. The amplitude of the sustained visuocortical response to a flickering stimulus (i.e., steady-state visually evoked potential [ssVEP] power) was examined in 39 participants while pupil diameter was measured. To generalize across stimulus conditions, Gabor stimuli varied in brightness and ssVEP driving frequency. As expected, brighter stimuli prompted pupil constriction and larger ssVEP power. To determine whether momentary fluctuations in pupil size contribute to the ssVEP amplitude under conditions of constant luminance and frequency, the single-trial means from each measure were correlated and the shape of the pupil-diameter waveform related to the ssVEP amplitude time course, both within and between participants. Under constant conditions, changes in pupil diameter were not related to changes in ssVEP amplitude, at any luminance level or driving frequency. Findings suggest that pupil dilation does not systematically prompt subsequent changes in visuocortical activity, and thus is not a sufficient cause of visuocortical modulation in cognitive or affective tasks.
| S-EPMC6012182 | biostudies-other
Project description:Background and objectiveExecutive dysfunction is the most common cognitive impairment in Parkinson's disease (PD), occurring even in its early stages. In our study, we applied diffusion tensor imaging (DTI) to investigate white matter integrity and its association with a specific executive function such as cognitive flexibility in individuals with risk factors for PD.MethodsWe examined 50 individuals with risk factors for developing PD and 24 healthy controls from the TREND (Tübinger Evaluation of Risk Factors for Early Detection of Neurodegeneration) study including neuropsychological evaluation and DTI. Cognitive flexibility was assessed using the trail making test (TMT). Tract based spatial statistics (TBSS) were employed to assess white matter abnormalities and their correlation with cognitive flexibility.ResultsTMT performance correlated with mean and axial diffusivity in several white matter regions, predominantly in the frontoparietal white matter. These effects were stronger in PD risk persons (PD-RP) than in controls as evidenced by a significant group interaction. White matter integrity and TMT performance did not significantly differ across groups.ConclusionBased on our results, PD-RP do no exhibit white matter changes or impaired cognitive flexibility. However, specific executive functions in PD-RP are more related to white matter alterations than in healthy older adults.
| S-EPMC7439016 | biostudies-literature