Journal of neurogenetics最新文献

Genes play an important role in the risk of Progressive Supranuclear Palsy (PSP). Some of the major risk genes identified for PSP include MAPT, STX6, MOBP, and EIF2AK3 in several ethnic groups. However, the interactions among these genes have not been explored in PSP. Therefore, this prospective case-control study aimed to explore the impact of gene-gene interactions in patients with PSP (n = 106) and healthy subjects (n = 109) of Indian ethnicity. Eight single nucleotide polymorphisms (SNPs) of MAPT gene (rs1467967, rs242557, rs3785883, rs2471738, rs8070723, rs7521, rs12185268, and rs62063857, and two SNPs of STX6 gene (rs3747957 and rs1411478), one SNP each from MOBP (rs1768208) and EIF2AK3 (rs7571971) genes were genotyped by TaqMan Alleleic Discrimination Assay in all the study participants. Gene-gene interactions among these 12 SNPs were performed using the multi-dimensionality reduction (MDR) test. The combination of SNPs from the MAPT gene (rs1467967, rs242557, rs3785883), along with STX6 (rs1411478) and MOBP (rs1768208), appeared to be the best five-locus model (p < 0.001), suggesting strong interactions among MAPT, STX6 and MOBP genes in modulating the risk of PSP. Strong synergistic interactions were observed within MAPT gene (rs1467967, rs244557, rs3785883, rs7521, and rs2471738), and between MAPT (rs7521) and MOBP (rs1768208). Additionally, moderately strong synergistic interactions were found between (i) MOBP (rs1768208) and STX6 (rs1411478), and (ii) MOBP (rs1768208) and MAPT (rs3785883) genes. The findings of this study suggest significant impact of gene-gene interactions amongst MAPT, STX6, and MOBP genes in modulating the risk of PSP. This implies that epistatic interactions might constitute an important mechanism in delineating the genetic basis of PSP.

Ribonucleoprotein granules (mRNP granules) are thought to contribute to the control of neuronal mRNA translation required for consolidation of long-term memories. Consistent with this, the function of Ataxin-2 in mRNA granule assembly has been shown to be required for long-term olfactory habituation (LTH) in Drosophila, a form of non-associative memory. Knockdown of Ataxin-2 in either local interneurons (LNs) or projection neurons (PNs) of the insect antennal lobe disrupts LTH while leaving short-term habituation intact, leading to a model in which Ataxin-dependent translational control is required in both presynaptic and postsynaptic elements of the LN-PN synapse, whose potentiation has been causally linked to LTH. Here we use novel and established methods for cell-type specific perturbation to ask: (a) whether Ataxin-2 controls mRNA granule assembly in cell types beyond the few that have been examined; and (b) whether it functions not only in LTH, but also for long-term olfactory associative memory (LTM). We show that Ataxin-2 controls mRNP granule assembly in additional neuronal types, namely Kenyon Cells (KCs) that encode associative memory, as well as more broadly in non-neuronal cells, e.g. in nurse cells in the egg chamber. Furthermore, selective knockdown of Atx2 in α/β and α'/β' KCs blocks appetitive long-term but not short-term associative memories. Taken together these observations support a hypothesis that Ataxin-2 dependent translational control is widely required across different mnemonic circuits for consolidation of respective forms of long-term memories.

Forgetting behavior is a common phenomenon that has been widely studied in various model organisms, including Caenorhabditis elegans (C. elegans), Drosophila, and mammals such as mice and humans. Understanding the mechanisms underlying forgetting can provide valuable insights into potential treatments for memory-related disorders. In this study, C. elegans was used as a model organism to establish a forgetting model based on the PA14 pathogen. A proteomic analysis of signaling pathways involved in forgetting revealed the role of the Arp2/3 complex in regulating pathogen-induced forgetting. Manipulation of genes encoding the components of the Arp2/3 complex (arx-1, arx-2, arx-3, arx-5, and arx-7) led to a reduction in the duration of pathogen-induced forgetting. Additionally, one hour after pathogen removal, a significant decrease in the mRNA levels of arx-5 and arx-7 was observed, along with a reduction in arx-2::mCherry fluorescence in specific tissues of C. elegans. This study demonstrates that C. elegans exhibits forgetting behavior towards PA14, with a forgetting duration of approximately 2 hours. Pathogen-induced forgetting is associated with an increase in heterogeneous proteins localized to the cytoskeleton. Moreover, the expression levels of genes related to the Arp2/3 complex (arx-1, arx-2, arx-3, arx-5, and arx-7) are reduced, inhibiting cytoskeleton nucleation in cells. This inhibition may contribute to the observed pathogen-induced forgetting in C. elegans in response to PA14.

Males transfer many components in seminal fluid along with sperm during mating. While sex peptide is well established as a key regulator of female reproductive behaviour and success, the roles of other seminal fluid components remain less understood. A new Drosophila study now reveals functions for a sexually transmitted sugar in providing nutritional value and acting on nutrient-sensing neurons in the brain to maximize reproductive success. Here, we highlight the key findings of this study and explore the potential role of this sugar in male quality assessment by females and in modulation of cryptic female choice.

Inherited prion diseases (IPD) secondary to mutations of the prion protein gene, PRNP, exhibit diverse clinical phenotypes, capable of mimicking numerous primary neurodegenerative conditions. We describe the clinical phenotype and neuropathological findings in a family from County Limerick in Ireland presenting with Alzheimer's disease-like cognitive decline and motor symptoms caused by a novel missense mutation of PRNP. This mutation occurs in the PRNP central lysine cluster (CLC; codon 101-110), resulting in substitution of threonine with isoleucine at codon 107 (T107I). This case series highlights that IPD can be hard to distinguish from overlapping clinical syndromes seen in other neurodegenerative diseases. We also discuss similarities and differences of the novel mutation T107I to other pathogenic mutations of the CLC of PRNP.

Pathogenic variants in WDFY3, a gene encoding for an autophagy adaptor termed ALFY, are linked to neurodevelopmental delay and altered brain size in human probands. While the role of WDFY3 loss-of-function is extensively studied in neurons, little is known about the effects of WDFY3 upregulation in different cell types of the central nervous system (CNS). We show that overexpression of the Drosophila melanogaster WDFY3 ortholog, Bchs, in either glia or neurons impaired autophagy and locomotion. Bchs glial overexpression also increased VNC size and glial nuclei number significantly, whereas neuronal Bchs overexpression affected wing and thorax morphology. We identified 79 genes that were differentially expressed and overlapped in flies that overexpress Bchs in glial and neuronal cells, respectively. Additionally, upon neuronal Bchs overexpression differentially expressed genes clustered in gene ontology categories associated with autophagy and mitochondrial function. Our data indicate that glial as well as neuronal Bchs upregulation can have detrimental outcomes on neural function.

Painful diabetic neuropathy (PDN) is a common complication in patients with type 2 diabetes mellitus (T2DM) with disruption of vitamin D (VD) activity as one of the risk factors. Active VD exerts its biological functions through the vitamin D receptor (VDR), which polymorphisms in the VDR gene can impair. This study aims to establish VDR FokI and ApaI polymorphisms as risk factors for PDN. This case-control study used samples from T2DM patients with and without PDN. Neuropathic pain was diagnosed using the DN4 questionnaire, while FokI and ApaI polymorphisms were examined using the Polymerase Chain Reaction-Restriction Fragment Length Polymorphism method. Other factors examined included gender, hypertension, current insulin use, obesity, HbA1c levels, and dyslipidemia. A total of 64 subjects were involved in the study. The FokI polymorphism (CT+TT genotype) was a significant risk factor for PDN (OR 4.20; 95% CI [1.47-11.94]; p = 0.012). The T allele in the FokI polymorphism significantly increased the risk of PDN by 2.8 times (OR 2.78; 95% CI [1.28-6.01], p = 0.014). The ApaI polymorphism was not significantly associated with PDN. Diabetes duration ≥4.5 years and uncontrolled diabetes were other significant risk factors for PDN. Multivariate analysis identified three significant variables: FokI polymorphism (OR 5.00; 95% CI [1.37-18.24], p = 0.015), insulin use (OR 4.95; 95% CI [1.37-17.87], p = 0.015), and uncontrolled diabetes (OR 3.47; 95% CI [1.03-11.69], p = 0.045). The VDR FokI polymorphism with the T allele is a significant genetic risk factor for PDN in T2DM patients. The VDR ApaI polymorphism was not a significant risk factor for PDN.

Leigh syndrome spectrum is the most common form of childhood-onset mitochondrial encephalopathy and is characterized by progressive neurodegeneration. Treatment options for this condition remain limited to date. Nonetheless, two lines of research endeavor in the past decade have shown encouraging results worthy of further investigations. First, therapeutic hypoxia appears to improve neurological outcomes, which is somewhat counterintuitive but supported by preclinical evidence. Furthermore, nicotinic acid or nicotinamide riboside could be an adjunctive therapy that enhances the neuroprotective effect of hypoxia. Second, preclinical studies and preliminary clinical experience suggest that sildenafil is potentially disease-modifying for Leigh syndrome. Sildenafil has already been used to treat pulmonary hypertension, and its repurposing for Leigh syndrome has been endorsed by European Medicines Agency. This perspective aims to raise awareness about these progresses, as well as to call for more clinical studies to ensure safe and effective implementation of these treatment approaches in clinical practice.