20 research outputs found
Reduction in the levels of CoQ biosynthetic proteins is related to an increase in lifespan without evidence of hepatic mitohormesis
Mitohormesis is an adaptive response induced by a mild mitochondrial stress that promotes longevity
and metabolic health in different organisms. This mechanism has been proposed as the cause of the
increase in the survival in Coq7+/â (Mclk1+/â) mice, which show hepatic reduction of COQ7, early
mitochondrial dysfunction and increased oxidative stress. Our study shows that the lack of COQ9 in
Coq9Q95X mice triggers the reduction of COQ7, COQ6 and COQ5, which results in an increase in life
expectancy. However, our results reveal that the hepatic CoQ levels are not decreased and, therefore,
neither mitochondrial dysfunction or increased oxidative stress are observed in liver of Coq9Q95X mice.
These data point out the tissue specific differences in CoQ biosynthesis. Moreover, our results suggest
that the effect of reduced levels of COQ7 on the increased survival in Coq9Q95X mice may be due to
mitochondrial mechanisms in non-liver tissues or to other unknown mechanisms.This work was supported by grants from Ministerio de
EconomĂa Competitividad, Spain, and the ERDF (Grant Number SAF2015-65786-R), from the ConsejeriÌa de
EconomiÌa, InnovacioÌn, Ciencia y Empleo, Junta de AndaluciÌa (grant number P10-CTS-6133) and from the
University of Granada (grant reference âUNETEâ, UCE-PP2017-06). AHG is a âFPU fellowâ from the Ministerio
de EducacioÌn Cultura y Deporte, Spain. MLS was a predoctoral fellow from the ConsejeriÌa de EconomiÌa,
InnovacioÌn, Ciencia y Empleo, Junta de AndaluciÌa. LCL was supported by the âRamoÌn y Cajalâ National
Programme, Ministerio de EconomiÌa y Competitividad, Spain (RYC-2011-07643)
Mitochondria function associated genes contribute to Parkinson's Disease risk and later age at onset
Mitochondrial dysfunction has been implicated in the etiology of monogenic Parkinsonâs disease (PD). Yet the role that
mitochondrial processes play in the most common form of the disease; sporadic PD, is yet to be fully established. Here, we
comprehensively assessed the role of mitochondrial function-associated genes in sporadic PD by leveraging improvements in the
scale and analysis of PD GWAS data with recent advances in our understanding of the genetics of mitochondrial disease. We
calculated a mitochondrial-specific polygenic risk score (PRS) and showed that cumulative small effect variants within both our
primary and secondary gene lists are significantly associated with increased PD risk. We further reported that the PRS of the
secondary mitochondrial gene list was significantly associated with later age at onset. Finally, to identify possible functional
genomic associations we implemented Mendelian randomization, which showed that 14 of these mitochondrial functionassociated genes showed functional consequence associated with PD risk. Further analysis suggested that the 14 identified genes
are not only involved in mitophagy, but implicate new mitochondrial processes. Our data suggests that therapeutics targeting
mitochondrial bioenergetics and proteostasis pathways distinct from mitophagy could be beneficial to treating the early
stage of PD
Moving beyond neurons: the role of cell type-specific gene regulation in Parkinson's disease heritability
Parkinsonâs disease (PD), with its characteristic loss of nigrostriatal dopaminergic neurons and deposition of α-synuclein in neurons, is often considered a neuronal disorder. However, in recent years substantial evidence has emerged to implicate glial cell types, such as astrocytes and microglia. In this study, we used stratified LD score regression and expression-weighted cell-type enrichment together with several brain-related and cell-type-specific genomic annotations to connect human genomic PD findings to specific brain cell types. We found that PD heritability attributable to common variation does not enrich in global and regional brain annotations or brain-related cell-type-specific annotations. Likewise, we found no enrichment of PD susceptibility genes in brain-related cell types. In contrast, we demonstrated a significant enrichment of PD heritability in a curated lysosomal gene set highly expressed in astrocytic, microglial, and oligodendrocyte subtypes, and in LoF-intolerant genes, which were found highly expressed in almost all tested cellular subtypes. Our results suggest that PD risk loci do not lie in specific cell types or individual brain regions, but rather in global cellular processes detectable across several cell types
Effect of air temperature on forecasting the start of Cupressaceae pollen type in Ponferrada [Leon, Spain]
In order to survive periods of adverse cold climatic conditions, plant requirements are satisfi ed by means of physiological adaptations to prevent cells from freezing. Thus, the growth of woody plants in temperate regions slows down and they enter into a physiological state called dormancy. In order to identify the chilling and heat requirements to overcome the dormancy period of Cupressaceae pollen type in the south of Europe, we have carried out our study with aerobiological data from a 10-year (1996- 2005) period in Ponferrada, LeĂłn (Spain). For the chilling requirements the best result was with a threshold temperature of 7.1ÂșC and an average of 927 CH. Calculation of heat requirements was carried out with maximum temperature, with 490 growth degree days (GDD) needed, with a threshold temperature of 0ÂșC. We have used the 2002-2003, 2003- 2004 and 2004-2005 periods in order to determine the real validity of the model. We have not used these years in developing the models. The dates predicted differ in only a few days from those observed: in 2002-2003 there was a difference of 11 days, in 2003-2004 predicted and observed dates were the same, but in 2004-2005 the difference obtained was of 43 days
The current coenzyme Q science and knowledge
Coenzyme Q (CoQ) is a redox lipid essential for aerobic respiration and antioxidant protection. It is synthesized in each cell by a multiprotein complex inside mitochondria and incorporated in all cellular membranes. It is however an amazing molecule whose homeostasis not only depends on the proper function of biosynthesis complex but also on age, diet and the wholeness of mitochondria functions
The Genetic Architecture of Parkinson Disease in Spain: Characterizing Population-Specific Risk, Differential Haplotype Structures, and Providing Etiologic Insight
Background:
The Iberian Peninsula stands out as having variable levels of population admixture and isolation, making Spain an interesting setting for studying the genetic architecture of neurodegenerative diseases. /
Objectives:
To perform the largest PD genomeâwide association study restricted to a single country. /
Methods:
We performed a GWAS for both risk of PD and age at onset in 7,849 Spanish individuals. Further analyses included populationâspecific risk haplotype assessments, polygenic risk scoring through machine learning, Mendelian randomization of expression, and methylation data to gain insight into diseaseâassociated loci, heritability estimates, genetic correlations, and burden analyses. /
Results:
We identified a novel populationâspecific genomeâwide association study signal at PARK2 associated with age at onset, which was likely dependent on the c.155delA mutation. We replicated four genomeâwide independent signals associated with PD risk, including SNCA, LRRK2, KANSL1/MAPT, and HLAâDQB1. A significant trend for smaller risk haplotypes at known loci was found compared to similar studies of nonâSpanish origin. Seventeen PDârelated genes showed functional consequence by twoâsample Mendelian randomization in expression and methylation data sets. Long runs of homozygosity at 28 known genes/loci were found to be enriched in cases versus controls. /
Conclusions:
Our data demonstrate the utility of the Spanish risk haplotype substructure for future fineâmapping efforts, showing how leveraging unique and diverse population histories can benefit genetic studies of complex diseases. The present study points to PARK2 as a major hallmark of PD etiology in Spain.