Adult Raphe-Specific Deletion of Lmx1b Leads to Central Serotonin Deficiency

The transcription factor Lmx1b is essential for the differentiation and survival of central serotonergic (5-HTergic) neurons during embryonic development. However, the role of Lmx1b in adult 5-HTergic neurons is unknown. We used an inducible Cre-LoxP system to selectively inactivate Lmx1b expression in the raphe nuclei of adult mice. Pet1-CreERT2 mice were generated and crossed with Lmx1bflox/flox mice to obtain Pet1-CreERT2; Lmx1bflox/flox mice (which termed as Lmx1b iCKO). After administration of tamoxifen, the level of 5-HT in the brain of Lmx1b iCKO mice was reduced to 60% of that in control mice, and the expression of tryptophan hydroxylase 2 (Tph2), serotonin transporter (Sert) and vesicular monoamine transporter 2 (Vmat2) was greatly down-regulated. On the other hand, the expression of dopamine and norepinephrine as well as aromatic L-amino acid decarboxylase (Aadc) and Pet1 was unchanged. Our results reveal that Lmx1b is required for the biosynthesis of 5-HT in adult mouse brain, and it may be involved in maintaining normal functions of central 5-HTergic neurons by regulating the expression of Tph2, Sert and Vmat2

Author Correction: Elucidating causative gene variants in hereditary Parkinson’s disease in the Global Parkinson’s Genetics Program (GP2)

Correction to: npj Parkinson’s Disease, published online 27 June 2023 In this article the Global Parkinson’s Genetics Program (GP2) members names and affiliations were missing in the main author list of the Original article which are listed in the below

Defining the causes of sporadic Parkinson’s disease in the global Parkinson’s genetics program (GP2)

\ua9 2023, Springer Nature Limited. The Global Parkinson’s Genetics Program (GP2) will genotype over 150,000 participants from around the world, and integrate genetic and clinical data for use in large-scale analyses to dramatically expand our understanding of the genetic architecture of PD. This report details the workflow for cohort integration into the complex arm of GP2, and together with our outline of the monogenic hub in a companion paper, provides a generalizable blueprint for establishing large scale collaborative research consortia

Multi-ancestry genome-wide association meta-analysis of Parkinson’s disease

\ua9 2023, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply. Although over 90 independent risk variants have been identified for Parkinson’s disease using genome-wide association studies, most studies have been performed in just one population at a time. Here we performed a large-scale multi-ancestry meta-analysis of Parkinson’s disease with 49,049 cases, 18,785 proxy cases and 2,458,063 controls including individuals of European, East Asian, Latin American and African ancestry. In a meta-analysis, we identified 78 independent genome-wide significant loci, including 12 potentially novel loci (MTF2, PIK3CA, ADD1, SYBU, IRS2, USP8, PIGL, FASN, MYLK2, USP25, EP300 and PPP6R2) and fine-mapped 6 putative causal variants at 6 known PD loci. By combining our results with publicly available eQTL data, we identified 25 putative risk genes in these novel loci whose expression is associated with PD risk. This work lays the groundwork for future efforts aimed at identifying PD loci in non-European populations

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)1.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field

Defining the causes of sporadic Parkinson’s disease in the global Parkinson’s genetics program (GP2)

The Global Parkinson’s Genetics Program (GP2) will genotype over 150,000 participants from around the world, and integrate genetic and clinical data for use in large-scale analyses to dramatically expand our understanding of the genetic architecture of PD. This report details the workflow for cohort integration into the complex arm of GP2, and together with our outline of the monogenic hub in a companion paper, provides a generalizable blueprint for establishing large scale collaborative research consortia

Author Correction: Elucidating causative gene variants in hereditary Parkinson’s disease in the Global Parkinson’s Genetics Program (GP2)

Correction to: s41531-023-00526-9 npj Parkinson’s Disease, published online 27 June 2023 In this article the Global Parkinson’s Genetics Program (GP2) members names and affiliations were missing in the main author list of the Original article which are listed in the below

Mitochondrial dysfunction and mitophagy in Parkinson's: from familial to sporadic disease.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterised by the preferential loss of dopaminergic neurons in the substantia nigra. Mitochondrial dysfunction is increasingly appreciated as a key determinant of dopaminergic neuronal susceptibility in PD and is a feature of both familial and sporadic disease, as well as in toxin-induced Parkinsonism. Recently, the mechanisms by which PD-associated mitochondrial proteins phosphatase and tensin homolog deleted on chromosome 10 (PTEN)-induced putative kinase 1 (PINK1) and parkin function and induce neurodegeneration have been identified. In addition, increasing evidence implicates other PD-associated proteins such as α-synuclein (α-syn) and leucine-rich repeat kinase 2 (LRRK2) in mitochondrial dysfunction in genetic cases of PD with the potential for a large functional overlap with sporadic disease. This review highlights how recent advances in understanding familial PD-associated proteins have identified novel mechanisms and therapeutic strategies for addressing mitochondrial dysfunction in PD

Asymptomatic bacteriuria in diabetes mellitus patients in Southwest Cameroon

Background: Asymptomatic bacteriuria (ASB) is common in diabetics and predisposes these patients to more severe urinary tract infections (UTIs). Reports on the prevalence and etiology of ASB especially in developing countries appear contradictory. Objectives: To determine the prevalence and etiology of ASB and antimicrobial resistance of urinary isolates in diabetics and non-diabetics. Methods: The study involved a total of 265 participants including 154 diabetes mellitus patients and 111 non-diabetics in Southwest Cameroon. Mid-stream urine was collected from consented subjects and each sample tested using the dipstick,microscopy and culture techniques. Isolates were identified using standard biochemical tests. Results: ASB was detected in 33.2% of participants; 38.3% in diabetics and 26.1% in non-diabetics (P = 0.03). Coagulasenegative staphylococci (CNS) were the predominant organisms (36.3%) isolated from urine in both diabetics and nondiabetics. Other isolates included Klebsiella sp (15.9%), Candida sp (13.7%), E. coli (10.8%) and Serratia sp (10.8%). Candida sp was isolated more from diabetics than non-diabetics (P = 0.01). There was no significant difference in resistance between diabetics and non-diabetics (P > 0.05). Most isolates showed multiple resistance and ciprofloxacin was the most active ingredient against bacterial uropathogens. Conclusion: The study revealed a high prevalence of ASB in diabetics than in non-diabetics. A change in the aetiologic spectrum was observed with Staphylococcus sp accounting for majority of ASB. Most isolates showed multiple resistance in both diabetics and non-diabetics; therefore the need to speed up sensitization against antibiotic abuse in Southwest Cameroon

Molecular markers for artemisinin and partner drug resistance in natural Plasmodium falciparum populations following increased insecticide treated net coverage along the slope of mount Cameroon: cross-sectional study

Background Drug resistance is one of the greatest challenges of malaria control programmes, with the monitoring of parasite resistance to artemisinins or to Artemisinin Combination Therapy (ACT) partner drugs critical for elimination efforts. Markers of resistance to a wide panel of antimalarials were assessed in natural parasite populations from southwestern Cameroon. Methods Individuals with asymptomatic parasitaemia or uncomplicated malaria were enrolled through cross-sectional surveys from May 2013 to March 2014 along the slope of mount Cameroon. P. falciparum malaria parasitaemic blood screened by light microscopy was depleted of leucocytes using CF11 cellulose columns and the parasite genotype ascertained by sequencing on the Illumina HiSeq platform. Results A total of 259 participants were enrolled in this study from three different altitudes. While some alleles associated with drug resistance in pfdhfr, pfmdr1 and pfcrt were highly prevalent, less than 3% of all samples carried mutations in the pfkelch13 gene, none of which were amongst those associated with slow artemisinin parasite clearance rates in Southeast Asia. The most prevalent pfcrt, pfmdr1, pfdhfr and pfdhps haplotypes were triple mutants for pfcrt-74, 75, and 76 i.e. C72V73I74E75T76 (47.3%), a single mutation at codon 184, N86F184D1246 (53.2%), the I51R59N108I164 (99%) and S436G437K540A581A613 (69%) variants in the genes respectively. Conclusions The predominance of the pfcrt CVIET and dhfr IRN triple mutant parasites and absence of pfkelch13 resistance alleles suggest that the amodiaquine and pyrimethamine components of AS-AQ and SP may no longer be effective in their role while chloroquine resistance still persists in southwestern Cameroon