Rubén Fernández-Santiago

Angiogenin variants in Parkinson disease and amyotrophic lateral sclerosis

Several studies have suggested an increased frequency of variants in the gene encoding angiogenin (ANG) in patients with amyotrophic lateral sclerosis (ALS). Interestingly, a few ALS patients carrying ANG variants also showed signs of Parkinson disease (PD). Furthermore, relatives of ALS patients have an increased risk to develop PD, and the prevalence of concomitant motor neuron disease in PD is higher than expected based on chance occurrence. We therefore investigated whether ANG variants could predispose to both ALS and PD.

Identification of blood serum micro-RNAs associated with idiopathic and LRRK2 Parkinson's disease.

Blood‐cell‐free circulating micro‐RNAs (miRNAs) have been proposed as potential accessible biomarkers for neurodegenerative diseases such as Parkinsons disease (PD). Here we analyzed the serum levels of 377 miRNAs in a discovery set of 10 idiopathic Parkinsons disease (IPD) patients, 10 PD patients carriers of the LRRK2 G2019S mutation (LRRK2 PD), and 10 controls by using real‐time quantitative PCR‐based TaqMan MicroRNA arrays. We detected candidate differentially expressed miRNAs, which were further tested in a first validation set consisting of 20 IPD, 20 LRRK2 PD, and 20 control samples. We found four statistically significant miRNAs that were downregulated in either LRRK2 or IPD (miR‐29a, miR‐29c, miR‐19a, and miR‐19b). Subsequently, we validated these findings in a third set of samples consisting of 65 IPD and 65 controls and confirmed the association of downregulated levels of miR‐29c, miR‐29a, and miR‐19b in IPD. Differentially expressed miRNAs are predicted to target genes belonging to pathways related to ECM–receptor interaction, focal adhesion, MAPK, Wnt, mTOR, adipocytokine, and neuron projection. Results from our exploratory study indicate that downregulated levels of specific circulating serum miRNAs are associated with PD and suggest their potential use as noninvasive biomarkers for PD. Future studies should further confirm the association of these miRNAs with PD.

Mutant superoxide dismutase-1 indistinguishable from wild-type causes ALS

A reason for screening amyotrophic lateral sclerosis (ALS) patients for mutations in the superoxide dismutase-1 (SOD1) gene is the opportunity to find novel mutations with properties that can give information on pathogenesis. A novel c.352C>G (L117V) SOD1 mutation was found in two Syrian ALS families living in Europe. The disease showed unusually low penetrance and slow progression. In erythrocytes, the total SOD1 activity, as well as specific activity of the mutant protein, was equal in carriers of the mutation and family controls lacking SOD1 mutations. The structural stabilities of the L117V mutant and wild-type SOD1 under denaturing conditions were likewise equal, but considerably lower than that of murine SOD1. As analyzed with an ELISA specific for misfolded SOD1 species, no differences were found in the content of misfolded SOD1 protein between extracts of fibroblasts from wild-type controls and from an L117V patient. In contrast, elevated levels of misfolded SOD1 protein were found in fibroblasts from ALS patients carrying seven other mutations in the SOD1 gene. We conclude that mutations in SOD1 that result in a fully stable protein are associated with low disease penetrance for ALS and may be found in cases of apparently sporadic ALS. Wild-type human SOD1 is moderately stable, and was found here to be within the stability range of ALS-causing SOD1 variants, lending support to the hypothesis that wild-type SOD1 could be more generally involved in ALS pathogenesis.

Aberrant epigenome in iPSC‐derived dopaminergic neurons from Parkinson's disease patients

The epigenomic landscape of Parkinsons disease (PD) remains unknown. We performed a genomewide DNA methylation and a transcriptome studies in induced pluripotent stem cell (iPSC)‐derived dopaminergic neurons (DAn) generated by cell reprogramming of somatic skin cells from patients with monogenic LRRK2‐associated PD (L2PD) or sporadic PD (sPD), and healthy subjects. We observed extensive DNA methylation changes in PD DAn, and of RNA expression, which were common in L2PD and sPD. No significant methylation differences were present in parental skin cells, undifferentiated iPSCs nor iPSC‐derived neural cultures not‐enriched‐in‐DAn. These findings suggest the presence of molecular defects in PD somatic cells which manifest only upon differentiation into the DAn cells targeted in PD. The methylation profile from PD DAn, but not from controls, resembled that of neural cultures not‐enriched‐in‐DAn indicating a failure to fully acquire the epigenetic identity own to healthy DAn in PD. The PD‐associated hypermethylation was prominent in gene regulatory regions such as enhancers and was related to the RNA and/or protein downregulation of a network of transcription factors relevant to PD (FOXA1, NR3C1, HNF4A, and FOSL2). Using a patient‐specific iPSC‐based DAn model, our study provides the first evidence that epigenetic deregulation is associated with monogenic and sporadic PD.

Sleep Disorders in Parkinsonian and Nonparkinsonian LRRK2 Mutation Carriers

Objective In idiopathic Parkinson disease (IPD) sleep disorders are common and may antedate the onset of parkinsonism. Based on the clinical similarities between IPD and Parkinson disease associated with LRRK2 gene mutations (LRRK2-PD), we aimed to characterize sleep in parkinsonian and nonmanifesting LRRK2 mutation carriers (NMC). Methods A comprehensive interview conducted by sleep specialists, validated sleep scales and questionnaires, and video-polysomnography followed by multiple sleep latency test (MSLT) assessed sleep in 18 LRRK2-PD (17 carrying G2019S and one R1441G mutations), 17 NMC (11 G2019S, three R1441G, three R1441C), 14 non-manifesting non-carriers (NMNC) and 19 unrelated IPD. Results Sleep complaints were frequent in LRRK2-PD patients; 78% reported poor sleep quality, 33% sleep onset insomnia, 56% sleep fragmentation and 39% early awakening. Sleep onset insomnia correlated with depressive symptoms and poor sleep quality. In LRRK2-PD, excessive daytime sleepiness (EDS) was a complaint in 33% patients and short sleep latencies on the MSLT, which are indicative of objective EDS, were found in 71%. Sleep attacks occurred in three LRRK2-PD patients and a narcoleptic phenotype was not observed. REM sleep behavior disorder (RBD) was diagnosed in three LRRK2-PD. EDS and RBD were always reported to start after the onset of parkinsonism in LRRK2-PD. In NMC, EDS was rarely reported and RBD was absent. When compared to IPD, sleep onset insomnia was more significantly frequent, EDS was similar, and RBD was less significantly frequent and less severe in LRRK2-PD. In NMC, RBD was not detected and sleep complaints were much less frequent than in LRRK2-PD. No differences were observed in sleep between NMC and NMNC. Conclusions Sleep complaints are frequent in LRRK2-PDand show a pattern that when compared to IPD is characterized by more frequent sleep onset insomnia, similar EDS and less prominent RBD. Unlike in IPD, RBD and EDS seem to be not markers of the prodromal stage of LRRK2-PD.

The MC1R melanoma risk variant p.R160W is associated with Parkinson disease

Epidemiological studies have reported the co‐occurrence of Parkinson disease (PD) and melanoma. Common genetic variants in the MC1R (melanocortin 1 receptor) gene, which determines skin and hair color, are associated with melanoma. Here we investigated whether genetic variants in MC1R modulate the risk of PD by sequencing the entire gene in 870 PD patients and 736 controls ascertained from Spain. We found that the MC1R variant p.R160W (rs1805008) is marginally associated with PD (odds ratiou2009=u20092.10, gender‐ and age‐adjusted pu2009=u20090.009, Bonferroni‐corrected pu2009=u20090.063). Our results suggest that MC1R genetic variants modulate the risk of PD disease in the Spanish population. Ann Neurol 2015;77:889–894

No evidence of association of FLJ10986 and ITPR2 with ALS in a large German cohort

A recent genome-wide association study (GWAS) found significant association of six single nucleotide polymorphisms (SNPs) in the gene FLJ10986 with sporadic amyotrophic lateral sclerosis (SALS). Another independent GWAS reported significant association of one SNP in the gene inositol 1,4,5-triphosphate receptor 2 (ITPR2) with SALS. These studies provided conflicting results. We examined the six most significant SNPs in FLJ10986 and one SNP in ITPR2 in a large cohort consisting of 595 SALS cases and 681 controls ascertained from Germany. Our results did not provide evidence for the association of these SNPs with SALS, suggesting a possible population-specific effect for FLJ10986 and ITPR2 that do not modulate the risk for SALS in the German population.

Motor and nonmotor heterogeneity of LRRK2‐related and idiopathic Parkinson's disease

Parkinsons disease (PD) associated with LRRK2 mutations has been described as similar to idiopathic PD with minor clinical differences. No study has compared the clinical features of LRRK2‐associated PD due to different mutations. The objective of this study was to compare LRRK2‐associated PD due to G2019S and G2385R mutations and to compare each to idiopathic PD.

Age at Onset in LRRK2-Associated PD is Modified by SNCA Variants

Mutations in the leucine-rich repeat kinase 2 (LRRK2) and α-synuclein (SNCA) genes are known genetic causes of Parkinsons disease (PD). Recently, a genetic variant in SNCA has been associated with a lower age at onset in idiopathic PD (IPD). We genotyped the SNCA polymorphism rs356219 in 84 LRRK2-associated PD patients carrying the G2019S mutation. We found that a SNCA genetic variant is associated with an earlier age at onset in LRRK2-associated PD. Our results support the notion that SNCA variants can modify the pathogenic effect of LRRK2 mutations as described previously for IPD.

The human G93A SOD1 phenotype closely resembles sporadic amyotrophic lateral sclerosis

Transgenic mouse models of human SOD1 mutations have opened up an area of intense investigation into the pathogenesis of familial and sporadic amyotrophic lateral sclerosis (ALS). However, the human phenotype of the G93A SOD1 mutation—the most commonly studied mutation in rodent models—has remained essentially unknown. This complicates the interpretation and transfer of results from animal models. Here clinical, electrophysiological and genealogical data are presented from a large German pedigree with a G93A mutation in the SOD1 gene. This pedigree shows a highly homogenous phenotype which closely resembles the typical phenotype of sporadic ALS, thus implicating comparable disease pathology of G93A SOD1 ALS and sporadic ALS.