Cerebrospinal fluid immunoglobulins in primary progressive multiple sclerosis are pathogenic.

Multiple sclerosis is clinically characterized by relapses and remissions (relapsing-remitting multiple sclerosis) that over time may evolve to a progressive course (secondary progressive multiple sclerosis) or as having a progressive course from disease onset (primary progressive multiple sclerosis). At present, it is not definitively known whether these clinical entities constitute a single pathological disease or whether these manifestations represent two distinct disease entities sharing inflammatory demyelination as a pathological feature. Here we show using a novel mouse model that CSF of primary progressive multiple sclerosis patients is unique in its capacity to induce motor disability and spinal cord pathology including demyelination, impaired remyelination, reactive astrogliosis and axonal damage. Notably, removal of immunoglobulin G from primary progressive multiple sclerosis CSF via filtration or immunodepletion attenuates its pathogenic capacity. Furthermore, injection of recombinant antibodies derived from primary progressive multiple sclerosis CSF recapitulates the pathology. Our findings suggest that the clinical and pathological features of primary progressive multiple sclerosis are antibody-mediated and pathogenically distinct from relapsing-remitting and secondary progressive multiple sclerosis. Our study has potentially important implications for the development of specific therapies for patients with primary progressive multiple sclerosis.

Apolipoprotein B-100-mediated motor neuron degeneration in sporadic amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis is a fatal neurodegenerative disease characterized by motor neuron degeneration. Approximately 90% of cases occur sporadically with no known cause while 10% are familial cases arising from known inherited genetic mutations. In vivo studies have predominantly utilized transgenic models harbouring amyotrophic lateral sclerosis-associated gene mutations, which have not hitherto elucidated mechanisms underlying motor neuron death or identified therapeutic targets specific to sporadic amyotrophic lateral sclerosis. Here we provide evidence demonstrating pathogenic differences in CSF from patients with sporadic amyotrophic lateral sclerosis and familial amyotrophic lateral sclerosis patients with mutations in SOD1, C9orf72 and TARDBP. Using a novel CSF-mediated animal model, we show that intrathecal delivery of sporadic amyotrophic lateral sclerosis patient-derived CSF into the cervical subarachnoid space in adult wild-type mice induces permanent motor disability which is associated with hallmark pathological features of amyotrophic lateral sclerosis including motor neuron loss, cytoplasmic TDP-43 translocation, reactive astrogliosis and microglial activation. Motor impairments are not induced by SOD1, C9orf72 or TARDBP CSF, although a moderate degree of histopathological change occurs in C9orf72 and TARDBP CSF-injected mice. By conducting a series of CSF filtration studies and global proteomic analysis of CSF, we identified apolipoprotein B-100 in sporadic amyotrophic lateral sclerosis CSF as the putative agent responsible for inducing motor disability, motor neuron degeneration and pathological translocation of TDP-43. Apolipoprotein B-100 alone is sufficient to recapitulate clinical and pathological outcomes in vivo and induce death of human induced pluripotent stem cell-derived motor neurons in vitro. Targeted removal of apolipoprotein B-100 from sporadic amyotrophic lateral sclerosis CSF via filtration or immunodepletion successfully attenuated the neurotoxic capacity of sporadic amyotrophic lateral sclerosis CSF to induce motor disability, motor neuron death, and TDP-43 translocation. This study presents apolipoprotein B-100 as a novel therapeutic target specific for the predominant sporadic form of amyotrophic lateral sclerosis and establishes proof-of-concept to support CSF pheresis as a therapeutic strategy for mitigating neurotoxicity in sporadic amyotrophic lateral sclerosis.

A Review of Oral Therapies for the Treatment of Skin Hyperpigmentation.

This review article examines evidence supporting the use of oral therapies in treating idiopathic, actinic, and metabolically induced skin hyperpigmentation. A thorough review of the literature regarding oral treatments for hyperpigmentation was systematically conducted through PubMed. Keywords used in the primary search include "Hyperpigmentation," "Melanosis" or "Melasma," "Lightening," "Oral," and "Therapeutics." The search was limited to the English language, and no timeframe restrictions were implemented. Numerous orally administered therapies have been proposed for the treatment of skin hyperpigmentation. There is an abundant body of literature demonstrating the efficacy of orally administered tranexamic acid, glutathione, isotretinoin, and proanthocyanidin. It is reasonable to expect that the most effective oral therapies will address known underlying causes of hyperpigmentation such as thyroid disease, diabetes, and hormonal imbalance. Improvement due to oral therapy of otherwise unresponsive skin hyperpigmentation or hyperpigmentation of unknown cause is less predictable. This review is limited by the strength of evidence contained within the available studies. Clinical studies investigating the treatments discussed within this article are limited in number, at times lack blinding in the study design, and are based on small sample sizes. Based on existing research, the most promising oral remedies for hyperpigmentation appear to be tranexamic acid, glutathione, isotretinoin, and proanthocyanidin. Additional studies to better establish safety and efficacy are necessary.

Genomics analysis of hexanoic acid exposure in Drosophila species.

Drosophila sechellia is a dietary specialist endemic to the Seychelles islands that has evolved to consume the fruit of Morinda citrifolia. When ripe, the fruit of M. citrifolia contains octanoic acid and hexanoic acid, two medium-chain fatty acid volatiles that deter and are toxic to generalist insects. Drosophila sechellia has evolved resistance to these volatiles allowing it to feed almost exclusively on this host plant. The genetic basis of octanoic acid resistance has been the focus of multiple recent studies, but the mechanisms that govern hexanoic acid resistance in D. sechellia remain unknown. To understand how D. sechellia has evolved to specialize on M. citrifolia fruit and avoid the toxic effects of hexanoic acid, we exposed adult D. sechellia, D. melanogaster and D. simulans to hexanoic acid and performed RNA sequencing comparing their transcriptional responses to identify D. sechellia specific responses. Our analysis identified many more genes responding transcriptionally to hexanoic acid in the susceptible generalist species than in the specialist D. sechellia. Interrogation of the sets of differentially expressed genes showed that generalists regulated the expression of many genes involved in metabolism and detoxification whereas the specialist primarily downregulated genes involved in the innate immunity. Using these data, we have identified interesting candidate genes that may be critically important in aspects of adaptation to their food source that contains high concentrations of HA. Understanding how gene expression evolves during dietary specialization is crucial for our understanding of how ecological communities are built and how evolution shapes trophic interactions.

Genomics Analysis of L-DOPA Exposure in Drosophila sechellia.

Drosophila sechellia is a dietary specialist fruit fly that evolved from a generalist ancestor to specialize on the toxic fruit of Morinda citrifolia This species pair has been the subject of numerous studies where the goal has largely been to determine the genetic basis of adaptations associated with host specialization. Because one of the most striking features of M. citrifolia fruit is the production of toxic volatile compounds that kill insects, most genomic studies in D. sechellia to date have focused on gene expression responses to the toxic compounds in its food. In this study, we aim to identify new genes important for host specialization by profiling gene expression response to 3,4-dihydroxyphenylalanine (L-DOPA). Recent work found it to be highly abundant in M. citrifolia, critical for reproductive success of D. sechellia, and supplementation of diet with the downstream pathway product dopamine can influence toxin resistance phenotypes in related species. Here we used a combination of functional genetics and genomics techniques to identify new genes that are important for D. sechellia ecological adaptation to this new niche. We show that L-DOPA exposure can affect toxin resistance phenotypes, identify genes with plastic responses to L-DOPA exposure, and functionally test an identified candidate gene. We found that knock-down of Esterase 6 (Est6) in a heterologous species alters toxin resistance suggesting Est6 may play an important role in D. sechellia host specialization.

Investigating the role of Osiris genes in Drosophila sechellia larval resistance to a host plant toxin.

The underlying genetic basis of adaptive phenotypic changes is generally poorly understood, yet a growing number of case studies are beginning to shed light on important questions about the molecular nature and pleiotropy of such changes. We use Drosophila sechellia, a dietary specialist fruit fly that evolved to specialize on a single toxic host plant, Morinda citrifolia, as a model for adaptive phenotypic change and seek to determine the genetic basis of traits associated with host specialization in this species. The fruit of M. citrifolia is toxic to other drosophilids, primarily due to high levels of the defense chemical octanoic acid (OA), yet D. sechellia has evolved resistance to OA. Our prior work identified three Osiris family genes that reside in a fine-mapped QTL for OA resistance: Osiris 6 (Osi6), Osi7, and Osi8, which can alter OA resistance in adult D. melanogaster when knocked down with RNA interference suggesting they may contribute to OA resistance in D. sechellia. Genetic mapping identified overlapping genomic regions involved in larval and adult OA resistance in D. sechellia, yet it remains unknown whether Osiris genes contribute to resistance in both life stages. Furthermore, because multiple genomic regions contribute to OA resistance, we aim to identify other gene(s) involved in this adaptation. Here, we identify candidate larval OA resistance genes using RNA sequencing to measure genome-wide differential gene expression in D. sechellia larvae after exposure to OA and functionally test identified genes for a role in OA resistance. We then test the Osiris genes previously shown to alter adult OA resistance for effects on OA resistance in larvae. We found that Osi8 knockdown decreased OA resistance in D. melanogaster larvae. These data suggest that evolved changes in Osi8 could impact OA resistance in multiple life stages while Osi6 and Osi7 may only impact adult resistance to OA.

Transcriptomic Analysis of Octanoic Acid Response in Drosophila sechellia Using RNA-Sequencing.

The dietary specialist fruit fly Drosophila sechellia has evolved to specialize on the toxic fruit of its host plant Morinda citrifolia Toxicity of Morinda fruit is primarily due to high levels of octanoic acid (OA). Using RNA interference (RNAi), prior work found that knockdown of Osiris family genes Osiris 6 (Osi6), Osi7, and Osi8 led to increased susceptibility to OA in adult D. melanogaster flies, likely representing genes underlying a Quantitative Trait Locus (QTL) for OA resistance in D. sechellia While genes in this major effect locus are beginning to be revealed, prior work has shown at least five regions of the genome contribute to OA resistance. Here, we identify new candidate OA resistance genes by performing differential gene expression analysis using RNA-sequencing (RNA-seq) on control and OA-exposed D. sechellia flies. We found 104 significantly differentially expressed genes with annotated orthologs in D. melanogaster, including six Osiris gene family members, consistent with previous functional studies and gene expression analyses. Gene ontology (GO) term enrichment showed significant enrichment for cuticle development in upregulated genes and significant enrichment of immune and defense responses in downregulated genes, suggesting important aspects of the physiology of D. sechellia that may play a role in OA resistance. In addition, we identified five candidate OA resistance genes that potentially underlie QTL peaks outside of the major effect region, representing promising new candidate genes for future functional studies.