Highlights d Loss of SETD5 impairs brain development and neuronal functions d Setd5 mutant mice exhibit cognitive and sociobehavioral deficits d SETD5 loss leads to an unfavorable chromatin state for RNA elongation and splicing d SETD5 has intrinsic histone methyltransferase activity for H3K36

The lack of technology for direct global-scale targeting of the adult mouse nervous system has hindered research on brain processing and dysfunctions. Currently, gene transfer is normally achieved by intraparenchymal viral injections, but these injections target a restricted brain area. Herein, we demonstrated that intravenous delivery of adeno-associated virus (AAV)-PHP.B viral particles permeated and diffused throughout the neural parenchyma, targeting both the central and the peripheral nervous system in a global pattern. We then established multiple procedures of viral transduction to control gene expression or inactivate gene function exclusively in the adult nervous system and assessed the underlying behavioral effects. Building on these results, we established an effective gene therapy strategy to counteract the widespread accumulation of α-synuclein deposits throughout the forebrain in a mouse model of synucleinopathy. Transduction of A53T-SCNA transgenic mice with AAV-PHP.B-GBA1 restored physiological levels of the enzyme, reduced α-synuclein pathology, and produced significant behavioral recovery. Finally, we provided evidence that AAV-PHP.B brain penetration does not lead to evident dysfunctions in blood-brain barrier integrity or permeability. Altogether, the AAV-PHP.B viral platform enables non-invasive, widespread, and long-lasting global neural expression of therapeutic genes, such as GBA1, providing an invaluable approach to treat neurodegenerative diseases with diffuse brain pathology such as synucleinopathies.

Given the recent in vitro discovery that the free soluble oligosaccharide of GM1 is the bioactive portion of GM1 for neurotrophic functions, we investigated its therapeutic potential in the B4galnt1+/− mice, a model of sporadic Parkinson’s disease. We found that the GM1 oligosaccharide, systemically administered, reaches the brain and completely rescues the physical symptoms, reduces the abnormal nigral α-synuclein content, restores nigral tyrosine hydroxylase expression and striatal neurotransmitter levels, overlapping the wild-type condition. Thus, this study supports the idea that the Parkinson’s phenotype expressed by the B4galnt1+/− mice is due to a reduced level of neuronal ganglioside content and lack of interactions between the oligosaccharide portion of GM1 with specific membrane proteins. It also points to the therapeutic potential of the GM1 oligosaccharide for treatment of sporadic Parkinson’s disease.

The Human Pain Genetics Database (HPGDB) is a comprehensive variant-focused inventory of genetic contributors to human pain. After curation, the HPGDB currently includes 294 studies reporting associations between 434 distinct genetic variants and various pain phenotypes. Variants were then submitted to a comprehensive analysis. First, they were validated in an independent high-powered replication cohort by testing the association of each variant with 10 different pain phenotypes (n = 1320-26,973). One hundred fifty-five variants replicated successfully (false discovery rate 20%) in at least one pain phenotype, and the association P values of the HPGDB variants were significantly lower compared with those of random controls. Among the 155 replicated variants, 21 had been included in the HPGDB because of their association with analgesia-related and 13 with nociception-related phenotypes, confirming analgesia and nociception as pathways of vulnerability for pain phenotypes. Furthermore, many genetic variants were associated with multiple pain phenotypes, and the strength of their association correlated between many pairs of phenotypes. These genetic variants explained a considerable amount of the variance between different pairs of pain phenotypes, indicating a shared genetic basis among pain phenotypes. In addition, we found that HPGDB variants show many pleiotropic associations, indicating that genetic pathophysiological mechanisms are also shared among painful and nonpainful conditions. Finally, we demonstrated that the HPGDB data set is significantly enriched for functional variants that modify gene expression, are deleterious, and colocalize with open chromatin regions. As such, the HPGDB provides a validated data set that represents a valuable resource for researchers in the human pain field.

Neuropeptide Y (NPY) is a neuropeptide abundantly expressed in the mammalian central and peripheral nervous system. NPY is a pleiotropic molecule, which influences cell proliferation, cardiovascular and metabolic function, pain and neuronal excitability. In the central nervous system, NPY acts as a neuromodulator, affecting pathways that range from cellular (excitability, neurogenesis) to circuit level (food intake, stress response, pain perception). NPY has a broad repertoire of receptor subtypes, each activating specific signaling pathways in different tissues and cellular sub-regions. In the context of epilepsy, NPY is thought to act as an endogenous anticonvulsant that performs its action through Y2 and Y5 receptors. In fact, its overexpression in the brain with the aid of viral vectors can suppress seizures in animal models of epilepsy. Therefore, NPY-based gene therapy may represent a novel approach for the treatment of epilepsy patients, particularly for pharmaco-resistant and genetic forms of the disease. Nonetheless, considering all the aforementioned aspects of NPY signaling, the study of possible NPY applications as a therapeutic molecule is not devoid of critical aspects. The present review will summarize data related to NPY biology, focusing on its anti-epileptic effects, with a critical appraisal of key elements that could be exploited to improve the already existing NPY-based gene therapy approaches for epilepsy.