Exploring the genetic and genomic connection underlying neurodegeneration with brain iron accumulation and the risk for Parkinson's disease.

Neurodegeneration with brain iron accumulation (NBIA) represents a group of neurodegenerative disorders characterized by abnormal iron accumulation in the brain. In Parkinson's Disease (PD), iron accumulation is a cardinal feature of degenerating regions in the brain and seems to be a key player in mechanisms that precipitate cell death. The aim of this study was to explore the genetic and genomic connection between NBIA and PD. We screened for known and rare pathogenic mutations in autosomal dominant and recessive genes linked to NBIA in a total of 4481 PD cases and 10,253 controls from the Accelerating Medicines Partnership Parkinsons' Disease Program and the UKBiobank. We examined whether a genetic burden of NBIA variants contributes to PD risk through single-gene, gene-set, and single-variant association analyses. In addition, we assessed publicly available expression quantitative trait loci (eQTL) data through Summary-based Mendelian Randomization and conducted transcriptomic analyses in blood of 1886 PD cases and 1285 controls. Out of 29 previously reported NBIA screened coding variants, four were associated with PD risk at a nominal p value < 0.05. No enrichment of heterozygous variants in NBIA-related genes risk was identified in PD cases versus controls. Burden analyses did not reveal a cumulative effect of rare NBIA genetic variation on PD risk. Transcriptomic analyses suggested that DCAF17 is differentially expressed in blood from PD cases and controls. Due to low mutation occurrence in the datasets and lack of replication, our analyses suggest that NBIA and PD may be separate molecular entities.

Seventy-Two-Hour LRRK2 Kinase Activity Inhibition Increases Lysosomal GBA Expression in H4, a Human Neuroglioma Cell Line.

Mutations in LRRK2 and GBA1 are key contributors to genetic risk of developing Parkinson's disease (PD). To investigate how LRRK2 kinase activity interacts with GBA and contributes to lysosomal dysfunctions associated with the pathology of PD. The activity of the lysosomal enzyme ß-Glucocerebrosidase (GCase) was assessed in a human neuroglioma cell model treated with two selective inhibitors of LRKK2 kinase activity (LRRK2-in-1 and MLi-2) and a GCase irreversible inhibitor, condutirol-beta-epoxide (CBE), under 24 and 72 h experimental conditions. We observed levels of GCase activity comparable to controls in response to 24 and 72 h treatments with LRRK2-in-1 and MLi-2. However, GBA protein levels increased upon 72 h treatment with LRRK2-in-1. Moreover, LC3-II protein levels were increased after both 24 and 72 h treatments with LRRK2-in-1, suggesting an activation of the autophagic pathway. These results highlight a possible regulation of lysosomal function through the LRRK2 kinase domain and suggest an interplay between LRRK2 kinase activity and GBA. Although further investigations are needed, the enhancement of GCase activity might restore the defective protein metabolism seen in PD.

Common and rare variants in HFE are not associated with Parkinson's disease in Europeans.

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.

Proteotoxicity and Neurodegenerative Diseases.

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.