Genomic profiling informs diagnoses and treatment in vascular anomalies.

Vascular anomalies are malformations or tumors of the blood or lymphatic vasculature and can be life-threatening. Although molecularly targeted therapies can be life-saving, identification of the molecular etiology is often impeded by lack of accessibility to affected tissue samples, mosaicism or insufficient sequencing depth. In a cohort of 356 participants with vascular anomalies, including 104 with primary complex lymphatic anomalies (pCLAs), DNA from CD31+ cells isolated from lymphatic fluid or cell-free DNA from lymphatic fluid or plasma underwent ultra-deep sequencing thereby uncovering pathogenic somatic variants down to a variant allele fraction of 0.15%. A molecular diagnosis, including previously undescribed genetic causes, was obtained in 41% of participants with pCLAs and 72% of participants with other vascular malformations, leading to a new medical therapy for 63% (43/69) of participants and resulting in improvement in 63% (35/55) of participants on therapy. Taken together, these data support the development of liquid biopsy-based diagnostic techniques to identify previously undescribed genotype-phenotype associations and guide medical therapy in individuals with vascular anomalies.

Transcriptome deregulation of peripheral monocytes and whole blood in GBA-related Parkinson's disease.

BACKGROUND: Genetic mutations in beta-glucocerebrosidase (GBA) represent the major genetic risk factor for Parkinson's disease (PD). GBA participates in both the endo-lysosomal pathway and the immune response, two important mechanisms involved in the pathogenesis of PD. However, modifiers of GBA penetrance have not yet been fully elucidated. METHODS: We characterized the transcriptomic profiles of circulating monocytes in a population of patients with PD and healthy controls (CTRL) with and without GBA variants (n = 23 PD/GBA, 13 CTRL/GBA, 56 PD, 66 CTRL) and whole blood (n = 616 PD, 362 CTRL, 127 PD/GBA, 165 CTRL/GBA). Differential expression analysis, pathway enrichment analysis, and outlier detection were performed. Ultrastructural characterization of isolated CD14+ monocytes in the four groups was also performed through electron microscopy. RESULTS: We observed hundreds of differentially expressed genes and dysregulated pathways when comparing manifesting and non-manifesting GBA mutation carriers. Specifically, when compared to idiopathic PD, PD/GBA showed dysregulation in genes involved in alpha-synuclein degradation, aging and amyloid processing. Gene-based outlier analysis confirmed the involvement of lysosomal, membrane trafficking, and mitochondrial processing in manifesting compared to non-manifesting GBA-carriers, as also observed at the ultrastructural levels. Transcriptomic results were only partially replicated in an independent cohort of whole blood samples, suggesting cell-type specific changes. CONCLUSIONS: Overall, our transcriptomic analysis of primary monocytes identified gene targets and biological processes that can help in understanding the pathogenic mechanisms associated with GBA mutations in the context of PD.

Dysregulation of mitochondrial and proteolysosomal genes in Parkinson's disease myeloid cells.

An increasing number of identified Parkinson's disease (PD) risk loci contain genes highly expressed in innate immune cells, yet their role in pathology is not understood. We hypothesize that PD susceptibility genes modulate disease risk by influencing gene expression within immune cells. To address this, we have generated transcriptomic profiles of monocytes from 230 individuals with sporadic PD and healthy subjects. We observed a dysregulation of mitochondrial and proteasomal pathways. We also generated transcriptomic profiles of primary microglia from brains of 55 subjects and observed discordant transcriptomic signatures of mitochondrial genes in PD monocytes and microglia. We further identified 17 PD susceptibility genes whose expression, relative to each risk allele, is altered in monocytes. These findings reveal widespread transcriptomic alterations in PD monocytes, with some being distinct from microglia, and facilitate efforts to understand the roles of myeloid cells in PD as well as the development of biomarkers.

Clemastine Enhances Myelination in the Prefrontal Cortex and Rescues Behavioral Changes in Socially Isolated Mice.

Altered myelin structure and oligodendrocyte function have been shown to correlate with cognitive and motor dysfunction and deficits in social behavior. We and others have previously demonstrated that social isolation in mice induced behavioral, transcriptional, and ultrastructural changes in oligodendrocytes of the prefrontal cortex (PFC). However, whether enhancing myelination and oligodendrocyte differentiation could be beneficial in reversing such changes remains unexplored. To test this hypothesis, we orally administered clemastine, an antimuscarinic compound that has been shown to enhance oligodendrocyte differentiation and myelination in vitro, for 2 weeks in adult mice following social isolation. Clemastine successfully reversed social avoidance behavior in mice undergoing prolonged social isolation. Impaired myelination was rescued by oral clemastine treatment, and was associated with enhanced oligodendrocyte progenitor differentiation and epigenetic changes. Clemastine induced higher levels of repressive histone methylation (H3K9me3), a marker for heterochromatin, in oligodendrocytes, but not neurons, of the PFC. This was consistent with the capability of clemastine in elevating H3K9 histone methyltransferases activity in cultured primary mouse oligodendrocytes, an effect that could be antagonized by cotreatment with muscarine. Our data suggest that promoting adult myelination is a potential strategy for reversing depressive-like social behavior. Significance statement: Oligodendrocyte development and myelination are highly dynamic processes influenced by experience and neuronal activity. However, whether enhancing myelination and oligodendrocyte differentiation is beneficial to treat depressive-like behavior has been unexplored. Mice undergoing prolonged social isolation display impaired myelination in the prefrontal cortex. Clemastine, a Food and Drug Administration-approved antimuscarinic compound that has been shown to enhance myelination under demyelinating conditions, successfully reversed social avoidance behavior in adult socially isolated mice. This was associated with enhanced myelination and oligodendrocyte differentiation in the prefrontal cortex through epigenetic regulation. Thus, enhancing myelination may be a potential means of reversing depressive-like social behavior.