The genetic landscape of Parkinson's disease Lunati, A.; Lesage, S.; Brice, A.
Revue neurologique,
November 2018, 2018-Nov, 2018-11-00, 20181101, 2018-11, Volume:
174, Issue:
9
Journal Article
Peer reviewed
Open access
The cause of Parkinson's disease (PD) remains unknown in most patients. Since 1997, with the first genetic mutation known to cause PD described in SNCA gene, many other genes with Mendelian ...inheritance have been identified. We summarize genetic, clinical and neuropathological findings related to the 27 genes reported in the literature since 1997, associated either with autosomal dominant (AD): LRRK2, SNCA, VPS35, GCH1, ATXN2, DNAJC13, TMEM230, GIGYF2, HTRA2, RIC3, EIF4G1, UCHL1, CHCHD2, and GBA; or autosomal recessive (AR) inheritance: PRKN, PINK1, DJ1, ATP13A2, PLA2G6, FBXO7, DNAJC6, SYNJ1, SPG11, VPS13C, PODXL, and PTRHD1; or an X-linked transmission: RAB39B. Clinical and neuropathological variability among genes is great. LRRK2 mutation carriers present a phenotype similar to those with idiopathic PD whereas, depending on the SNCA mutations, the phenotype ranges from early onset typical PD to dementia with Lewy bodies, including many other atypical forms. DNAJC6 nonsense mutations lead to a very severe phenotype whereas DNAJC6 missense mutations cause a more typical form. PRKN, PINK1 and DJ1 cases present with typical early onset PD with slow progression, whereas other AR genes present severe atypical Parkinsonism. RAB39B is responsible for a typical phenotype in women and a variable phenotype in men. GBA is a major PD risk factor often associated with dementia. A growing number of reported genes described as causal genes (DNAJC13, TMEM230, GIGYF2, HTRA2, RIC3, EIF4G1, UCHL1, and CHCHD2) are still awaiting replication or indeed have not been replicated, thus raising questions as to their pathogenicity. Phenotypic data collection and next generation sequencing of large numbers of cases and controls are needed to differentiate pathogenic dominant mutations with incomplete penetrance from rare, non-pathogenic variants. Although known genes cause a minority of PD cases, their identification will lead to a better understanding their pathological mechanisms, and may contribute to patient care, genetic counselling, prognosis determination and finding new therapeutic targets.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Research in Parkinson's disease (PD) genetics has been extremely prolific over the past decade. More than 13 loci and 9 genes have been identified, but their implication in PD is not always certain. ...Point mutations, duplications and triplications in the α-synuclein (SNCA) gene cause a rare dominant form of PD in familial and sporadic cases. Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are a more frequent cause of autosomal dominant PD, particularly in certain ethnic groups. Loss-of-function mutations in Parkin, PINK1, DJ-1 and ATP13A2 cause autosomal recessive parkinsonism with early-onset. Identification of other Mendelian forms of PD will be a main challenge for the next decade. In addition, susceptibility variants that contribute to PD have been identified in several populations, such as polymorphisms in the SNCA, LRRK2 genes and heterozygous mutations in the β-glucocerebrosidase (GBA) gene. Genome-wide associations and re-sequencing projects, together with gene-environment interaction studies, are expected to further define the causal role of genetic determinants in the pathogenesis of PD, and improve prevention and treatment.
Glucocerebrosidase (GBA) gene mutations represent a strong risk factor for Parkinson disease (PD). PD penetrance in GBA mutation carriers, which represents a key issue for genetic counseling, ...especially for relatives of patients with Gaucher disease (GD), is unknown. Our objective was to estimate PD penetrance in a familial study of GBA mutation carriers.
Probands with familial PD were recruited through the French Parkinson Disease Genetic Study Group. All GBA exons were sequenced in probands and their relatives. To estimate the age-specific cumulative PD risk (i.e., penetrance) in GBA mutation carriers, we used the proband's phenotype exclusion likelihood method and corrected for selection of familial cases by considering the status of one affected relative per family as unknown.
Of 525 probands with familial PD, 24 (4.6%) were GBA mutation carriers. Of their 256 relatives, 43 (16.8%) had PD and 26 of 32 affected relatives tested for GBA mutations were mutation carriers; 213 relatives did not have PD and 31 of 71 of unaffected relatives tested for GBA mutations were mutation carriers. Under a dominant model, penetrance was estimated as 7.6%, 13.7%, 21.4%, and 29.7% at 50, 60, 70, and 80 years, respectively. There was no significant difference in penetrance at 70 years between N370S carriers, L444P carriers, and carriers of rarer mutations.
The relatively high penetrance estimate in GBA carriers obtained in this study should lead to consideration of GBA as a dominant causal gene with reduced penetrance and should be taken into account for genetic counseling in relatives of patients with GD and patients with GBA-associated PD.
Abstract
We present the systematic spectral analyses of gamma-ray bursts (GRBs) detected by the Fermi Gamma-Ray Burst Monitor during its first ten years of operation. This catalog contains two types ...of spectra: time-integrated spectral fits and spectral fits at the brightest time bin, from 2297 GRBs, resulting in a compendium of over 18,000 spectra. The four different spectral models used for fitting the spectra were selected based on their empirical importance to the shape of many GRBs. We describe in detail our procedure and criteria for the analyses, and present the bulk results in the form of parameter distributions both in the observer frame and in the GRB rest frame. 941 GRBs from the first four years have been refitted using the same methodology as that of the 1356 GRBs in years five through ten. The data files containing the complete results are available from the High-Energy Astrophysics Science Archive Research Center.
Abstract
Observing gravitationally lensed objects in the time domain is difficult, and well-observed time-varying sources are rare. Lensed gamma-ray bursts (GRBs) offer improved timing precision for ...this class of objects, complementing observations of quasars and supernovae. The rate of lensed GRBs is highly uncertain, approximately one in 1000. The Gamma-ray Burst Monitor on board the Fermi Gamma-ray Space Telescope has observed more than 3000 GRBs, making it an ideal instrument to uncover lensed bursts. Here we present observations of GRB 210812A showing two emission episodes, separated by 33.3 s and with a flux ratio of about 4.5. An exhaustive temporal and spectral analysis shows that the two emission episodes have the same pulse and spectral shape, which poses challenges to GRB models. We report multiple lines of evidence for a gravitational lens origin. In particular, modeling the lightcurve using nested sampling, we uncover strong evidence in favor of the lensing scenario. Assuming a point-mass lens, the mass of the lensing object is about 1 million solar masses. High-resolution radio imaging is needed for future lens candidates to derive tighter constraints.
Because retinal and cerebral arterioles share similar pathologic processes, retinal microvascular changes are expected to be markers of cerebral small vessel disease (SVD). To better understand the ...role of SVD in cognitive function, we investigated the relationship between retinal microvascular abnormalities and longitudinal changes in cognitive function in a community-based study.
A total of 803 participants underwent 4 cognitive assessments between 1990-1992 and 2004-2006, using the Word Fluency (WF) test, Digit Symbol Substitution (DSS), and Delayed Word Recall as well as retinal photography in 1993-1995. Covariate adjusted random effects linear models for repeated measures were used to determine the associations of cognitive change with specific retinal vascular abnormalities.
Individuals with retinopathy showed declines in executive function and psychomotor speed, with 1) an average decline in WF of -1.64 words per decade (95% confidence interval CI -3.3, -0.02) compared to no decline in those without retinopathy +0.06 (95% CI -0.6, 0.8) and 2) a higher frequency of rapid decliners on the DSS test.
Signs of retinal vascular changes, as markers of the cerebral microvasculature, are associated with declines in executive function and psychomotor speed, adding to the growing evidence for the role of microvascular disease in cognitive decline in the elderly.
The Hunga Tonga–Hunga Ha’apai submarine volcano recently resumed activity. Violent eruptions on 2022 January 14th and 15th launched a tall ash plume that produced extremely high lightning rates. Here ...we report a terrestrial gamma-ray flash (TGF) that was produced by the volcanic lightning and observed from space by the Fermi Gamma-ray Burst Monitor (GBM). Observations by radio lightning networks and especially by the Geostationary Lightning Mapper (GLM) show that the only lightning close enough to produce a TGF detectable by Fermi GBM was from the volcano’s plume. With the observing duration of Fermi, observing a single TGF is consistent with the hypothesis that the volcanic lightning of this eruption produced TGFs at the average rate of thunderstorm lightning. The observation of a strong TGF from space also indicates that the electric field was oriented so as to accelerate electrons upward.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Abstract
The recent discovery of a kilonova from the long-duration gamma-ray burst (GRB) GRB 211211A challenges classification schemes based on temporal information alone. Gamma-ray properties of GRB ...211211A reveal an extreme event, which stands out among both short and long GRBs. We find very short variations (few milliseconds) in the lightcurve of GRB 211211A and estimate ∼1000 for the Lorentz factor of the outflow. We discuss the relevance of the short variations in identifying similar long GRBs resulting from compact mergers. Our findings indicate that in future gravitational-wave follow-up campaigns, some long-duration GRBs should be treated as possible strong gravitational-wave counterparts.
Wheat kernel texture, a major trait determining the end-use quality of wheat flour, is mainly influenced by puroindolines. These small basic proteins displayin vitrolipid binding and antimicrobial ...properties, but their cellular functions during grain development remain unknown. To gain an insight into their biological function, a comparative proteome analysis of two near-isogenic lines (NILs) of bread wheatTriticum aestivumL. cv. Falcon differing in the presence or absence of the puroindoline-a gene (Pina) and kernel hardness, was performed. Proteomes of the two NILs were compared at four developmental stages of the grain for the metabolic albumin/globulin fraction and the Triton-extracted amphiphilic fraction. Proteome variations showed that, during grain development, folding proteins and stress-related proteins were more abundant in the hard line compared with the soft one. These results, taken together with ultrastructural observations showing that the formation of the protein matrix occurred earlier in the hard line, suggested that a stress response, possibly the unfolded protein response, is induced earlier in the hard NIL than in the soft one leading to earlier endosperm cell death. Quantification of the albumin/globulin fraction and amphiphilic proteins at each developmental stage strengthened this hypothesis as a plateau was revealed from the 500 °Cd stage in the hard NIL whereas synthesis continued in the soft one. These results open new avenues concerning the function of puroindolines which could be involved in the storage protein folding machinery, consequently affecting the development of wheat endosperm and the formation of the protein matrix.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
One of the most challenging applications for tissue regeneration is spinal cord damage. There is no cure for this, partly because cavities and scar tissue formed after injury present formidable ...barriers that must be crossed by axons to restore function. Natural silks are considered increasingly for medical applications because they are biocompatible, biodegradable and in selected cases promote tissue growth. Filaments from wild Antheraea pernyi silkworms can support axon regeneration in peripheral nerve injury. Here we presented evidence that degummed A. pernyi filaments (DAPF) support excellent outgrowth of CNS neurons in vitro by cell attachment to the high density of arginine-glycine-aspartic acid tripeptide present in DAPF. Importantly, DAPF showed stiffness properties that are well suited to spinal cord repair by supporting cell growth mechano-biology. Furthermore, we demonstrated that DAPF induced no activation of microglia, the CNS resident immune cells, either in vitro when exposed to DAPF or in vivo when DAPF were implanted in the cord. In vitro DAPF degraded gradually with a corresponding decrease in tensile properties. We conclude that A. pernyi silk meets the major biochemical and biomaterial criteria for spinal repair, and may have potential as a key component in combinatorial strategies for spinal repair.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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