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[Background] Previous studies linked disease-progression variables such as age at onset or survival to both genetic, and non-genetic factors in Parkinson's disease (PD) patients., [Objective] The aim of this study was to assess how genetic and non genetic factors act as modifiers of age at onset and survival and in a cohort of 753 PD patients, and to determine how these variables interact to define the overall risk., [Methods] We analyzed the effect of gender, tobacco, alcohol, type of PD (genetic, gPD or idiopathic, iPD) and three genetic variants rs5848- GRN, rs1042522- TP53 and APOE. We studied two cohorts (PPMI and IPDGC) to replicate positive results., [Results] Regarding age at onset, male smokers PD had a significantly lower mean age compared to non-smoker (p = 0.001). APOE-Ɛ4 carriers had a younger onset-age compared to non-carriers (p = 0.03) in the Spanish cohort, but these results were not replicated in the other cohorts. Concerning survival, PD patients with an early onset (below 50 years) had an increased survival rate (p < 0.001)., [Conclusions] Our study showed how several genetic and non-genetic risk factors influenced the age at onset and survival in PD., Irene Rosas was supported by a grant from Fundación Jose Luis Castaño-SEQC. Sergio Pérez-Oliveira is supported by Fundación Parkinson Asturias-Obra Social Cajastur. This study was supported by grant PI 15/00878 (Fondos Feder) to VA.

Lysosomal dysfunction has been proposed as one of the most important pathogenic molecular mechanisms in Parkinson disease (PD). The most significant evidence lies in the GBA gene, which encodes for the lysosomal enzyme beta-glucocerebrosidase (beta-GCase), considered the main genetic risk factor for sporadic PD. The loss of beta-GCase activity results in the formation of alpha-synuclein deposits. The present study was aimed to determine the activity of the main lysosomal enzymes and the cofactors Prosaposin (PSAP) and Saposin C in PD and healthy controls, and their contribution to alpha-synuclein (alpha-Syn) aggregation. 42 PD patients and 37 age-matched healthy controls were included in the study. We first analyzed the beta-GCase, beta-galactosidase (beta-gal), beta-hexosaminidase (Hex B) and Cathepsin D (CatD) activities in white blood cells. We also measured the GBA, beta-GAL, beta-HEX, CTSD, PSAP, Saposin C and alpha-Syn protein levels by Western-blot. We found a 20% reduced beta-GCase and beta-gal activities in PD patients compared to controls. PSAP and Saposin C protein levels were significantly lower in PD patients and correlated with increased levels of alpha-synuclein. CatD, in contrast, showed significantly increased activity and protein levels in PD patients compared to controls. Increased CTSD protein levels in PD patients correlated, intriguingly, with a higher concentration of alpha-Syn. Our findings suggest that lysosomal dysfunction in sporadic PD is due, at least in part, to an alteration in Saposin C derived from reduced PSAP levels. That would lead to a significant decrease in the beta-GCase activity, resulting in the accumulation of alpha-syn. The accumulation of monohexosylceramides might act in favor of CTSD activation and, therefore, increase its enzymatic activity. The evaluation of lysosomal activity in the peripheral blood of patients is expected to be a promising approach to investigate pathological mechanisms and novel therapies aimed to restore the lysosomal function in sporadic PD., Foundation "Progreso y Salud" of the Junta de Andalucia PI-0424-2014, FEDER/Junta de Andalucia-Consejeria de Transformacion Economica, Industria, Conocimiento y Universidades/Proyecto B-CTS-702-UGR20, German Research Foundation (DFG) FPU14/03473 EST16/00809

A recent study suggested that the p.H63D variant in HFE, a gene involved in iron homeostasis, may modify α-synuclein pathology, the pathological hallmark of Parkinson’s disease (PD). If indeed this gene and specific variant are involved in PD, we expect to find differential distribution of HFE variants when comparing PD patients and controls. We analyzed genome-wide association study (GWAS) data from 14,671 PD patients and 17,667 controls and full sequencing data from additional 1,647 PD patients and 1,050 controls, using logistic regression models, and burden and Kernel tests. The HFE p.H63D variant was not associated with PD, nor did all the other common variants in the HFE locus. We did not find association of rare HFE variants with PD as well in all types of burden and Kernel tests. Our results do not support a role for HFE in PD.

A recent study suggested that the p.H63D variant in HFE, a gene involved in iron homeostasis, may modify α‐synuclein pathology, the pathological hallmark of Parkinson's disease (PD). If indeed this gene and specific variant are involved in PD, we expect to find differential distribution of HFE variants when comparing PD patients and controls. We analyzed genome-wide association study (GWAS) data from 14,671 PD patients and 17,667 controls and full sequencing data from additional 1647 PD patients and 1050 controls, using logistic regression models, and burden and Kernel tests. The HFE p.H63D variant was not associated with PD, nor did all the other common variants in the HFE locus. We did not find association of rare HFE variants with PD as well in all types of burden and Kernel tests. Our results do not support a role for HFE in PD risk.

Neurodegenerative diseases are a major burden for our society, affecting millions of people worldwide. A main goal of past and current research is to enhance our understanding of the mechanisms underlying proteotoxicity, a common theme among these incurable and debilitating conditions. Cell proteome alteration is considered to be one of the main driving forces that triggers neurodegeneration, and unraveling the biological complexity behind the affected molecular pathways constitutes a daunting challenge. This review summarizes the current state on key processes that lead to cellular proteotoxicity in Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis, providing a comprehensive landscape of recent literature. A foundational understanding of how proteotoxicity affects disease etiology and progression may provide essential insight towards potential targets amenable of therapeutic intervention.

Parkinson's disease (PD) is the second most common neurodegenerative disease, whose prevalence is projected to be between 8.7 and 9.3 million by 2030. Until about 20 years ago, PD was considered to be the textbook example of a "non-genetic" disorder. Nowadays, PD is generally considered a multifactorial disorder that arises from the combination and complex interaction of genes and environmental factors. To date, a total of 7 genes including SNCA, LRRK2, PARK2, DJ-1, PINK 1, VPS35 and ATP13A2 have been seen to cause unequivocally Mendelian PD. Also, variants with incomplete penetrance in the genes LRRK2 and GBA are considered to be strong risk factors for PD worldwide. Although genetic studies have provided valuable insights into the pathogenic mechanisms underlying PD, the role of structural variation in PD has been understudied in comparison with other genomic variations. Structural genomic variations might substantially account for such genetic substrates yet to be discovered. The present review aims to provide an overview of the structural genomic variants implicated in the pathogenesis of PD.

In the recent years, the emergence of new technologies has revolutionized our concepts to identify genetic mechanisms implicated in Parkinson's disease (PD). Genome-wide association studies (GWAS) have been key in such enormous advance. To the best of our knowledge we have conducted the first GWAS of PD in a Spanish population. We replicated the association of 5 reported PD-related loci at nominal p-value, and our cumulative risk score was consistent with studies performed in other European populations. We did not manage to identify any novel rare variant through single variant and gene-based tests and we assume that there may be structural genomic variation conferring risk for PD poorly covered or undetectable by the array. We conclude that in complex genetic disorders such as PD, collaboration drives progress and real advances can only be made by large consortiums cooperating with collaborative spirit. In the years to come, interpretation of the risk in the context of disease pathogenesis will be the main goal to reach.