An exploration of knowledge, risk perceptions, and communication in a family with multiple genetic risks for Parkinson's disease.

Genomic testing increasingly challenges health care providers and patients to understand, share, and use information. The provision of polygenic risks is anticipated to complicate comprehension, communication, and risk perception further. This manuscript aims to illuminate the challenges confronting families with multiple genetic risks for Parkinson's disease. Identifying and planning for such issues may prove valuable to family members now and in the future, should neuroprotective or genotype-specific therapies become available. We present qualitative data from interviews with a multi-generational family carrying pathogenic variants in the glucocerebrosidase (GBA1) and leucine-rich repeat kinase 2 (LRRK2) genes which are associated with an increased risk for developing Parkinson's disease (PD). The family includes two brothers (heterozygous for LRRK2 p.G2019S and homozygous for GBA1 p.N409S) and their four descendants. The brothers were concordant for GD and discordant for PD. Genetic counseling and testing were provided to four of the six participants. Two years later, semi-structured interviews were conducted with the initial participants (n = 4) and two additional first-degree relatives. Interviews were transcribed and thematically analyzed, providing the basis for this report. Illuminated topics include the perceived risk of developing PD, recall of genetic information, and family communication. With the expanding use of exome and genome sequencing, we anticipate that genetic counselors will increasingly face the challenges demonstrated by this case involving multiple genetic risks for PD, limited data to clarify risk, and the inherent variability of family communication, genetic knowledge, and risk perception. This clinical case report provides a compelling narrative demonstrating the need for additional research exploring these multifaceted topics relevant to both families facing these challenges and providers striving to assist, support and guide their journey.

mTOR Modulation of IKr through hERG1b-Dependent Mechanisms in Lipotoxic Heart.

In the atria, the rapid delayed rectifier channel (IKr) is a critical contributor to repolarization. In lipotoxic atria, increased activity of the serine/threonine mammalian target of rapamycin (mTOR) may remodel IKr and predispose patients to arrhythmias. To investigate whether mTOR produced defects in IKr channel function (protein expression and gating mechanisms), electrophysiology and biochemical assays in HEK293 cells stably expressing hERG1a/1b, and adult guinea pig atrial myocytes were used. Feeding with the saturated fatty acid palmitic acid high-fat diet (HFD) was used to induce lipotoxicity. Lipotoxicity-challenged HEK293 cells displayed an increased density of hERG1a/1b currents due to a targeted and significant increase in hERG1b protein expression. Furthermore, lipotoxicity significantly slowed the hERG1a/1b inactivation kinetics, while the activation and deactivation remained essentially unchanged. mTOR complex 1 (mTORC1) inhibition with rapamycin (RAP) reversed the increase in hERG1a/1b density and inactivation. Compared to lipotoxic myocytes, RAP-treated cells displayed action potential durations (APDs) and IKr densities similar to those of controls. HFD feeding triggered arrhythmogenic changes (increased the IKr density and shortened the APD) in the atria, but this was not observed in low-fat-fed controls. The data are the first to show the modulation of IKr by mTORC1, possibly through the remodeling of hERG1b, in lipotoxic atrial myocytes. These results offer mechanistic insights with implications for targeted therapeutic options for the therapy of acquired supraventricular arrhythmias in obesity and associated pathologies.

Behavioral Phenotyping in a Murine Model of GBA1-Associated Parkinson Disease.

Mutations in GBA1, the gene encoding glucocerebrosidase, are common genetic risk factors for Parkinson disease (PD). While the mechanism underlying this relationship is unclear, patients with GBA1-associated PD often have an earlier onset and faster progression than idiopathic PD. Previously, we modeled GBA1-associated PD by crossing gba haploinsufficient mice with mice overexpressing a human mutant α-synuclein transgene (SNCAA53T), observing an earlier demise, shorter life span and faster symptom progression, although behavioral testing was not performed. To assess whether gba+/-//SNCAA53T mice exhibit a prodromal behavioral phenotype, we studied three cardinal PD features: olfactory discrimination, memory dysfunction, and motor function. The longitudinal performance of gba+/-//SNCAA53T (n = 8), SNCAA53T (n = 9), gba+/- (n = 10) and wildtype (n = 6) mice was evaluated between ages 8 and 23 months using the buried pellet test, novel object recognition test and the beam walk. Fifteen-month-old gba+/-//SNCAA53T mice showed more olfactory and motor deficits than wildtype mice. However, differences between gba+/-//SNCAA53T and SNCAA53T mice generally did not reach statistical significance, possibly due to small sample sizes. Furthermore, while gba haploinsufficiency leads to a more rapid demise, this might not result in an earlier prodromal stage, and other factors, including aging, oxidative stress and epigenetics, may contribute to the more fulminant disease course.

Macrophage-Dependent Interleukin-6-Production and Inhibition of IK Contributes to Acquired QT Prolongation in Lipotoxic Guinea Pig Heart.

In the heart, the delayed rectifier K current, IK, composed of the rapid (IKr) and slow (IKs) components contributes prominently to normal cardiac repolarization. In lipotoxicity, chronic elevation of pro-inflammatory cytokines may remodel IK, elevating the risk for ventricular arrythmias and sudden cardiac death. We investigated whether and how the pro-inflammatory interleukin-6 altered IK in the heart, using electrophysiology to evaluate changes in IK in adult guinea pig ventricular myocytes. We found that palmitic acid (a potent inducer of lipotoxicity), induced a rapid (~24 h) and significant increase in IL-6 in RAW264.7 cells. PA-diet fed guinea pigs displayed a severely prolonged QT interval when compared to low-fat diet fed controls. Exposure to isoproterenol induced torsade de pointes, and ventricular fibrillation in lipotoxic guinea pigs. Pre-exposure to IL-6 with the soluble IL-6 receptor produced a profound depression of IKr and IKs densities, prolonged action potential duration, and impaired mitochondrial ATP production. Only with the inhibition of IKr did a proarrhythmic phenotype of IKs depression emerge, manifested as a further prolongation of action potential duration and QT interval. Our data offer unique mechanistic insights with implications for pathological QT interval in patients and vulnerability to fatal arrhythmias.

Genetically and clinically confirmed atypical cerebrotendinous xanthomatosis with normal cholestanol and marked elevations of bile acid precursors and bile alcohols.

BACKGROUND: Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive lipid disorder. Affected patients often remain undiagnosed until the age of 20-30 years, when they have already developed significant neurologic disease that may not be reversible. An elevated plasma cholestanol concentration has been accepted as a diagnostic criterion for CTX for decades. OBJECTIVE: Full biochemical characterization was performed for three genetically and clinically confirmed atypical CTX cases with normal plasma cholestanol levels. METHODS: Clinical assessment and genetic/biochemical testing for patients with CTX was performed by their physician providing routine standard of care. RESULTS: We report three new atypical CTX cases with large extensor tendon xanthomas but normal plasma cholestanol levels. All three cases had marked elevations of bile acid precursors and bile alcohols in plasma and urine that decreased on treatment with chenodeoxycholic acid. We also review eight published cases of atypical CTX with normal/near normal circulating cholestanol levels. CONCLUSION: The atypical biochemical presentation of these cases provides a diagnostic challenge for CTX, a disorder for which cholestanol has been believed to be a sensitive biomarker. These cases demonstrate measurements of plasma cholestanol alone are insufficient to exclude a diagnosis of CTX. The data presented is consistent with the concept that bile acid precursors and bile alcohols are sensitive biomarkers for atypical CTX with normal cholestanol, and that such testing is indicated, along with CYP27A1 gene analyses, in patients presenting with significant tendon and/or tuberous xanthomas and/or neurologic disease in early adulthood despite normal or near normal cholesterol and cholestanol levels.

Variants in the WDR44 WD40-repeat domain cause a spectrum of ciliopathy by impairing ciliogenesis initiation.

WDR44 prevents ciliogenesis initiation by regulating RAB11-dependent vesicle trafficking. Here, we describe male patients with missense and nonsense variants within the WD40 repeats (WDR) of WDR44, an X-linked gene product, who display ciliopathy-related developmental phenotypes that we can model in zebrafish. The patient phenotypic spectrum includes developmental delay/intellectual disability, hypotonia, distinct craniofacial features and variable presence of brain, renal, cardiac and musculoskeletal abnormalities. We demonstrate that WDR44 variants associated with more severe disease impair ciliogenesis initiation and ciliary signaling. Because WDR44 negatively regulates ciliogenesis, it was surprising that pathogenic missense variants showed reduced abundance, which we link to misfolding of WDR autonomous repeats and degradation by the proteasome. We discover that disease severity correlates with increased RAB11 binding, which we propose drives ciliogenesis initiation dysregulation. Finally, we discover interdomain interactions between the WDR and NH2-terminal region that contains the RAB11 binding domain (RBD) and show patient variants disrupt this association. This study provides new insights into WDR44 WDR structure and characterizes a new syndrome that could result from impaired ciliogenesis.

Complete mitochondrial genome of the introduced Indian walking stick Carausius morosus (Lonchodidae, Insecta) from California.

We present the complete mitochondrial genome of Carausius morosus from Salinas, CA. The mitochondrial genome of C. morosus is circular, AT rich (78.1%), and 16,671 bp in length. It consists of 13 protein-coding, 22 transfer RNA, and 2 ribosomal RNA genes and is identical in gene content to Carausius sp.

Pro-cathepsin D, Prosaposin, and Progranulin: Lysosomal Networks in Parkinsonism.

Mutations in GBA1, the gene encoding the lysosomal hydrolase glucocerebrosidase (GCase), are a risk factor for parkinsonism. Pursuing the potential mechanisms underlying this risk in aging neurons, we propose a new network uniting three major lysosomal proteins: (i) cathepsin D (CTSD), which plays a major role in α-synuclein (SNCA) degradation and prosaposin (PSAP) cleavage; (ii) PSAP, essential for GCase activation and progranulin (PGRN) transport; and (iii) PGRN, impacting lysosomal biogenesis, PSAP trafficking, and CTSD maturation. We hypothesize that alterations to this network and associated receptors modify lysosomal function and subsequently impact both SNCA degradation and GCase activity. By exploring the interactions between this protein trio and each of their respective transporters and receptors, we may identify secondary risk factors that provide insight into the relationship between these lysosomal proteins, GCase, and SNCA, and reveal novel therapeutic targets.

Glucocerebrosidase as a therapeutic target for Parkinson's disease.

Introduction: The association between Gaucher disease, caused by the inherited deficiency of glucocerebrosidase, and Parkinson's disease was first recognized in the clinic, noting that patients with Gaucher disease and their carrier relatives had an increased incidence of Parkinson's disease. Currently, mutations in glucocerebrosidase (GBA1) are the most common genetic risk factor for Parkinson's disease and dementia with Lewy bodies, with an inverse relationship between glucocerebrosidase and α-synuclein, a key factor in Parkinson pathogenesis. The hypothesis that therapeutic enhancement of brain glucocerebrosidase levels might reduce the aggregation, accumulation or spread of α-synuclein has spurred great interest in glucocerebrosidase as a novel therapeutic target.Area covered: This article explores the potential molecular mechanisms underlying the association between GBA1 mutations and Parkinson's disease and outlines therapeutic strategies to increase brain glucocerebrosidase, including gene therapy, targeted delivery of recombinant glucocerebrosidase to the brain, small-molecule chaperones to rescue mutant glucocerebrosidase, and small-molecule modulators to activate wild-type glucocerebrosidase.Expert opinion: Although an improved understanding of the mechanistic basis for GBA1-associated parkinsonism is essential, enhancing levels of brain glucocerebrosidase may have wide therapeutic implications. While gene therapy may ultimately be effective, less expensive and invasive small-molecule non-inhibitory chaperones or activators could significantly impact the disease course.

Glucocerebrosidase and its relevance to Parkinson disease.

Mutations in GBA1, the gene encoding the lysosomal enzyme glucocerebrosidase, are among the most common known genetic risk factors for the development of Parkinson disease and related synucleinopathies. A great deal is known about GBA1, as mutations in GBA1 are causal for the rare autosomal storage disorder Gaucher disease. Over the past decades, significant progress has been made in understanding the genetics and cell biology of glucocerebrosidase. A least 495 different mutations, found throughout the 11 exons of the gene are reported, including both common and rare variants. Mutations in GBA1 may lead to degradation of the protein, disruptions in lysosomal targeting and diminished performance of the enzyme in the lysosome.Gaucher disease is phenotypically diverse and has both neuronopathic and non-neuronopathic forms. Both patients with Gaucher disease and heterozygous carriers are at increased risk of developing Parkinson disease and Dementia with Lewy Bodies, although our understanding of the mechanism for this association remains incomplete. There appears to be an inverse relationship between glucocerebrosidase and α-synuclein levels, and even patients with sporadic Parkinson disease have decreased glucocerebrosidase. Glucocerebrosidase may interact with α-synuclein to maintain basic cellular functions, or impaired glucocerebrosidase could contribute to Parkinson pathogenesis by disrupting lysosomal homeostasis, enhancing endoplasmic reticulum stress or contributing to mitochondrial impairment. However, the majority of patients with GBA1 mutations never develop parkinsonism, so clearly other risk factors play a role. Treatments for Gaucher disease have been developed that increase visceral glucocerebrosidase levels and decrease lipid storage, although they have yet to properly address the neurological defects associated with impaired glucocerebrosidase. Mouse and induced pluripotent stem cell derived models have improved our understanding of glucocerebrosidase function and the consequences of its deficiency. These models have been used to test novel therapies including chaperone proteins, histone deacetylase inhibitors, and gene therapy approaches that enhance glucocerebrosidase levels and could prove efficacious in the treatment of forms of parkinsonism. Consequently, this rare monogenic disorder, Gaucher disease, provides unique insights directly applicable to our understanding and treatment of Parkinson disease, a common and complex neurodegenerative disorder.

Can GBA1-Associated Parkinson Disease Be Modeled in the Mouse?

Homozygous and heterozygous mutations in GBA1, the gene implicated in Gaucher disease, increase the risk and severity of Parkinson disease (PD). We evaluated the design, phenotype, strengths, and limitations of current GBA1-associated PD mouse models. Although faithful modeling of a genetic risk factor poses many challenges, the different approaches taken were successful in revealing predisposing abnormalities in heterozygotes for GBA1 mutations and demonstrating the deleterious effects of GBA1 impairment on the PD course in PD models. GBA1-PD models differ in key parameters, with no single model recapitulating all aspects of the GBA1-PD puzzle, emphasizing the importance of selecting the proper in vivo model depending on the specific molecular mechanism or potential therapy being studied.