Mycotoxin contamination in organic and conventional cereal grain and products: A systematic literature review and meta-analysis.

There is still considerable controversy about the relative risk of mycotoxin exposure associated with the consumption of organic and conventional cereals. Using validated protocols, we carried out a systematic literature review and meta-analyses of data on the incidence and concentrations of mycotoxins produced by Fusarium, Claviceps, Penicillium, and Aspergillus species in organic and conventional cereal grains/products. The standard weighted meta-analysis of concentration data detected a significant effect of production system (organic vs. conventional) only for the Fusarium mycotoxins deoxynivalenol, with concentrations ∼50% higher in conventional than organic cereal grains/products (p < 0.0001). Weighted meta-analyses of incidence data and unweighted meta-analyses of concentration data also detected small, but significant effects of production system on the incidence and/or concentrations of T-2/HT-2 toxins, zearalenone, enniatin, beauvericin, ochratoxin A (OTA), and aflatoxins. Multilevel meta-analyses identified climatic conditions, cereal species, study type, and analytical methods used as important confounding factors for the effects of production system. Overall, results from this study suggest that (i) Fusarium mycotoxin contamination decreased between the 1990s and 2020, (ii) contamination levels are similar in organic and conventional cereals used for human consumption, and (iii) maintaining OTA concentrations below the maximum contamination levels (3.0 µg/kg) set by the EU remains a major challenge.

Optimal Volume Assessment for Serous Fluid Cytology.

OBJECTIVE: This study aimed to investigate the optimal volume of serous fluid needed for accurate diagnosis using The International System for Reporting Serous Fluid Cytopathology (TIS), as well as to provide information on the distribution of serous effusion cases in the TIS categories (ND: non-diagnostic, NFM: negative for malignancy, AUS: atypia of undetermined significance, SFM: suspicious for malignancy, MAL: malignant) and relevant epidemiological data. METHODS: A retrospective analysis of 2340 serous effusion cases (pleural, peritoneal, and pericardial) from two hospitals between 2018 and 2020 was conducted. TIS categories were assigned to each case, and for 1181 cases, these were correlated with the volume of the analyzed fluid. RESULTS: Our study found statistically significant differences in volume distributions between certain TIS categories. Statistically lower volumes were observed in NFM compared to MAL, in UNCERTAIN (ND, AUS, SFM) compared to both MAL and NFM, and in NOT MAL (ND, NFM, AUS, SFM) compared to MAL. However, these differences were not substantial enough to hold any clinical relevance. CONCLUSIONS: This study suggests that while fluid volume may slightly influence the TIS category, it does not impact the diagnostic accuracy of serous effusion cytology. Therefore, the ideal serous effusion specimen volume can be defined solely by practical parameters.

Effects of Agricultural Intensification on Mediterranean Diets: A Narrative Review.

INTRODUCTION: Mediterranean diets (MedDiets) are linked to substantial health benefits. However, there is also growing evidence that the intensification of food production over the last 60 years has resulted in nutritionally relevant changes in the composition of foods that may augment the health benefits of MedDiets. OBJECTIVE: To synthesize, summarize, and critically evaluate the currently available evidence for changes in food composition resulting from agricultural intensification practices and their potential impact on the health benefits of MedDiets. METHODS: We summarized/synthesized information from (i) systematic literature reviews/meta-analyses and more recently published articles on composition differences between conventional and organic foods, (ii) desk studies which compared food composition data from before and after agricultural intensification, (iii) recent retail and farm surveys and/or factorial field experiments that identified specific agronomic practices responsible for nutritionally relevant changes in food composition, and (iv) a recent systematic literature review and a small number of subsequently published observational and dietary intervention studies that investigated the potential health impacts of changes in food composition resulting from agricultural intensification. RESULTS AND DISCUSSION: There has been growing evidence that the intensification of food production has resulted in (i) lower concentrations of nutritionally desirable compounds (e.g., phenolics, certain vitamins, mineral micronutrients including Se, Zn, and omega-3 fatty acids, α-tocopherol) and/or (ii) higher concentrations of nutritionally undesirable or toxic compounds (pesticide residues, cadmium, omega-6 fatty acids) in many of the foods (including wholegrain cereals, fruit and vegetables, olive oil, dairy products and meat from small ruminants, and fish) that are thought to contribute to the health benefits associated with MedDiets. The evidence for negative health impacts of consuming foods from intensified conventional production systems has also increased but is still limited and based primarily on evidence from observational studies. Limitations and gaps in the current evidence base are discussed. Conclusions: There is now substantial evidence that the intensification of agricultural food production has resulted in a decline in the nutritional quality of many of the foods that are recognized to contribute to the positive health impacts associated with adhering to traditional MedDiets. Further research is needed to quantify to what extent this decline augments the positive health impacts of adhering to a traditional MedDiet.

Breeding Bread-Making Wheat Varieties for Organic Farming Systems: The Need to Target Productivity, Robustness, Resource Use Efficiency and Grain Quality Traits.

Agronomic protocols (rotation, tillage, fertilization and crop protection) commonly used in organic and conventional crop production differ significantly and there is evidence that modern varieties developed for conventional high-input farming systems do not have the combination of traits required for optimum performance in organic farming systems. Specifically, there is evidence that prohibition on the use of water-soluble, mineral N, P and K fertilizers and synthetic pesticide inputs in organic farming results in a need to revise both breeding and selection protocols. For organic production systems, the focus needs to be on the following: (i) traits prioritized by organic farmers such as high nutrient use efficiency from organic fertilizer inputs, competitiveness against weeds, and pest and disease resistance, (ii) processing quality parameters defined by millers and bakers and (iii) nutritional quality parameters demanded by organic consumers. In this article, we review evidence from variety trials and factorial field experiments that (i) studied to what extent there is a need for organic farming focused breeding programs, (ii) investigated which traits/trait combinations should be targeted in these breeding programs and/or (iii) compared the performance of modern varieties developed for the conventional sector with traditional/older varieties favored by organic farmers and/or new varieties developed in organic farming focused breeding programs. Our review focuses on wheat because there have been organic and/or low-input farming focused wheat breeding programs for more than 20 years in Europe, which has allowed the performance of varieties/genotypes from organic/low-input and conventional farming focused breeding programs to be compared.

Diet, but not food type, significantly affects micronutrient and toxic metal profiles in urine and/or plasma; a randomized, controlled intervention trial.

BACKGROUND: Observational studies have linked Mediterranean Diets (MedDiets) and organic food consumption with positive health outcomes, which may be explained by higher mineral micronutrient and phenolic intake and lower dietary exposure to toxic compounds. OBJECTIVES: We aimed to determine the effects of diet and food type (organic compared with conventional) on urinary excretion (UE) and/or plasma concentrations of mineral micronutrients, phenolics, and toxic metals. METHODS: Healthy adult participants were randomly allocated to a conventional (n = 14) or an intervention (n = 13) group. During a 2-wk period, the intervention group consumed a MedDiet made entirely from organic foods, whereas the conventional group consumed a MedDiet made from conventional foods. Before and after the intervention period, both groups consumed their habitual Western diets made from conventional foods. The primary outcome was UE and/or plasma concentrations of selected mineral micronutrients, toxic metals, and phenolic markers. In addition, we monitored diets using food diaries. The participants were aware of study group assignment, but the study assessors were not. RESULTS: Changing from a Western Diet to a MedDiet for 2 wk resulted in significant increases in UE of total phenolics and salicylic acid (by 46% and 45%, respectively), the mineral micronutrients Co, I, and Mn (by 211%, 70%, and 102%, respectively), and the toxic metal Ni (by 42%), and plasma Se concentrations (by 14%). However, no significant effects of food type (organic compared with conventional) were detected. Redundancy analysis identified vegetables, coffee, wine, and fruit as positive drivers for UE of phenolic markers and mineral micronutrients, and fish consumption as a positive driver for UE of Cd and Pb. CONCLUSIONS: Although small effects of food type cannot be ruled out, our study suggests that only changing to a MedDiet with higher fruit and vegetable, and lower meat, consumption results in a large increase in phenolic and mineral micronutrient intakes. This trial was registered at clinicaltrials.gov as NCT03254537.

Diet and food type affect urinary pesticide residue excretion profiles in healthy individuals: results of a randomized controlled dietary intervention trial.

BACKGROUND: Observational studies have linked pesticide exposure to various diseases, whereas organic food consumption has been associated with positive health outcomes. Organic farming standards prohibit the use of most pesticides, and organic food consumption may therefore reduce pesticide exposure. OBJECTIVES: To determine the effects of diet (Western compared with Mediterranean) and food type (conventional compared with organic) and sex on urinary pesticide residue excretion (UPRE), as well as associations between specific diet components and UPRE. METHODS: In this 2-wk, randomized dietary intervention trial, healthy adults were randomly allocated to an intervention (n = 13) or conventional (n = 14) group. Whereas participants in the intervention group consumed a Mediterranean diet (MedDiet) made entirely from organic foods, the conventional group consumed a MedDiet made entirely from conventional foods. Both groups consumed habitual Western diets made from conventional foods before and after the 2-wk intervention period. The primary outcome was UPRE. In addition, we assessed diet composition and pesticide residue profiles in foods eaten. Participants were aware of group assignment, but the study assessors were not. RESULTS: During the intervention period, total UPRE was 91% lower with organic (mean 17 µg/d; 95% CI: 15, 19) than with conventional (mean 180 µg/d; 95% CI: 153, 208) food consumption (P < 0.0001). In the conventional group, switching from the habitual Western diet to the MedDiet increased insecticide excretion from 7 to 25 µg/d (P < 0.0001), organophosphate excretion from 5 to 19 µg/d (P < 0.0001), and pyrethroid residue excretion from 2.0 to 4.5 µg/d (P < 0.0001). Small but significant effects of sex were detected for chlormequat, herbicide, and total pesticide residue excretion. CONCLUSIONS: Changing from a habitual Western diet to a MedDiet was associated with increased insecticide, organophosphate, and pyrethroid exposure, whereas organic food consumption reduced exposure to all groups of synthetic chemical pesticides. This may explain the positive health outcomes linked to organic food consumption in observational studies. This trial was registered at www.clinicaltrials.gov as NCT03254537.

Disease Duration Influences Gene Expression in Neuromelanin-Positive Cells From Parkinson's Disease Patients.

Analyses of gene expression in cells affected by neurodegenerative disease can provide important insights into disease mechanisms and relevant stress response pathways. Major symptoms in Parkinson's disease (PD) are caused by the degeneration of midbrain dopamine (mDA) neurons within the substantia nigra. Here we isolated neuromelanin-positive dopamine neurons by laser capture microdissection from post-mortem human substantia nigra samples recovered at both early and advanced stages of PD. Neuromelanin-positive cells were also isolated from individuals with incidental Lewy body disease (ILBD) and from aged-matched controls. Isolated mDA neurons were subjected to genome-wide gene expression analysis by mRNA sequencing. The analysis identified hundreds of dysregulated genes in PD. Results showed that mostly non-overlapping genes were differentially expressed in ILBD, subjects who were early after diagnosis (less than five years) and those autopsied at more advanced stages of disease (over five years since diagnosis). The identity of differentially expressed genes suggested that more resilient, stably surviving DA neurons were enriched in samples from advanced stages of disease, either as a consequence of positive selection of a less vulnerable long-term surviving mDA neuron subtype or due to up-regulation of neuroprotective gene products.

Effect of irrigation, fertiliser type and variety on grain yield and nutritional quality of spelt wheat (Triticum spelta) grown under semi-arid conditions.

Previous studies reported higher antioxidant and mineral micronutrient concentrations in organic compared to conventional wheat flour, but the reasons are poorly understood. Here we report results from a long-term, factorial field experiment designed to assess effects of variety choice, supplementary irrigation and contrasting fertilization regimes used in organic and conventional production on the nutritional quality and yield of spelt wheat grown in a semi-arid environment. Long-straw (Oberkulmer, Rubiota, ZOR) varieties had 10-40% higher grain Cu, Fe, Mn and Zn concentrations, while the modern, short straw variety Filderstolz had 15-38% higher grain antioxidant activity. Supplementary irrigation and the use of manure instead of mineral NPK as fertilizer had no substantial effect on the nutritional composition of spelt grain, but increased grain yields by ~ 150 and ~ 18% respectively. Overall, this suggests that breeding/variety selection is the most promising approach to improve the nutritional quality of spelt grain in semi-arid production environments.

Effect of Organic and Conventional Production Methods on Fruit Yield and Nutritional Quality Parameters in Three Traditional Cretan Grape Varieties: Results from a Farm Survey.

The antioxidants found in grapes and wine have been linked to health benefits in humans, but may be affected by agronomic parameters, grape type/variety, and processing. Here, we report results of a farm survey which investigated the effects of production system (organic vs. conventional) and grape variety on fruit yield, total antioxidant activity/capacity (TAA, assessed by the Trolox Equivalent Antioxidant Capacity (TEAC) and 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assays), and total concentrations of total phenolics (TPC) and anthocyanins (TAC) in grapes of one red (Kotsifali) and two white (Villana and/or Vidiano) traditional Cretan grape varieties. Analysis of variance (ANOVA) results showed that grape variety choice had a more substantial effect on TPC, TAA, and TAC than primary production protocols, and significant interactions were identified between production system and grape variety choice for TAATEAC. Specifically, TAATEAC was significantly (57%) higher in organic than conventional Vidiano grapes, while there was no significant effect of production system on TAATEAC in Kotsifali and Villana grapes. As expected from previous studies, the TAC was substantially higher in red Kotsifali grapes. Redundancy analysis (RDA) identified grape variety as the only strong explanatory variable/driver for yield, TPC, TAA, and TAC of table grapes, and positive associations were detected between the variety Vidiano and both TPC and TAATEAC. All other explanatory variables included in the RDA (including supplementary irrigation, orchard orientation, production system, soil type, vineyard age, plant density, and fertiliser inputs) explained only a small proportion of the additional variation.

Effects of Production Region, Production Systems and Grape Type/Variety on Nutritional Quality Parameters of Table Grapes; Results from a UK Retail Survey.

Grapes contain high concentrations of secondary metabolites and antioxidants that have been linked to a reduction of several chronic diseases. Here, we report results of a UK retail survey, which investigated the effect of the production region (Mediterranean vs. South Africa), grape type (white vs. red vs. black) and variety, and production system (organic vs. conventional) on antioxidant activity and concentrations of phenolic compounds in table grapes. Black grapes had ~180% total antioxidant activity (TAA), ~60% higher total phenolic content (TPC) and ~40 times higher anthocyanin concentrations (TAC) than white grapes, while red grapes had intermediate levels of TAA, TPC and TAC. The effects of season and production system and differences between varieties of the same grape type were substantially smaller. Grapes imported from Mediterranean countries in summer had a 14% higher TPC and ~20% higher TAA than grapes imported from South Africa in winter, and organic grapes had a 16% higher TPC and 22% higher TAA, but ~30% lower TAC than conventional grapes. Significant differences in TPC, TAA and/or TAC between organic and conventional grapes could only be detected for specific grape types, varieties and/or sampling years.

Author Correction: Single cell transcriptomics identifies stem cell-derived graft composition in a model of Parkinson's disease.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Single cell transcriptomics identifies stem cell-derived graft composition in a model of Parkinson's disease.

Cell replacement is a long-standing and realistic goal for the treatment of Parkinson's disease (PD). Cells for transplantation can be obtained from fetal brain tissue or from stem cells. However, after transplantation, dopamine (DA) neurons are seen to be a minor component of grafts, and it has remained difficult to determine the identity of other cell types. Here, we report analysis by single-cell RNA sequencing (scRNA-seq) combined with comprehensive histological analyses to characterize intracerebral grafts from human embryonic stem cells (hESCs) and fetal tissue after functional maturation in a pre-clinical rat PD model. We show that neurons and astrocytes are major components in both fetal and stem cell-derived grafts. Additionally, we identify a cell type closely resembling a class of recently identified perivascular-like cells in stem cell-derived grafts. Thus, this study uncovers previously unknown cellular diversity in a clinically relevant cell replacement PD model.

Single-cell RNA sequencing reveals midbrain dopamine neuron diversity emerging during mouse brain development.

Midbrain dopamine (mDA) neurons constitute a heterogenous group of cells that have been intensely studied, not least because their degeneration causes major symptoms in Parkinson's disease. Understanding the diversity of mDA neurons - previously well characterized anatomically - requires a systematic molecular classification at the genome-wide gene expression level. Here, we use single cell RNA sequencing of isolated mouse neurons expressing the transcription factor Pitx3, a marker for mDA neurons. Analyses include cells isolated during development up until adulthood and the results are validated by histological characterization of newly identified markers. This identifies seven neuron subgroups divided in two major branches of developing Pitx3-expressing neurons. Five of them express dopaminergic markers, while two express glutamatergic and GABAergic markers, respectively. Analysis also indicate evolutionary conservation of diversity in humans. This comprehensive molecular characterization will provide a valuable resource for elucidating mDA neuron subgroup development and function in the mammalian brain.

Effects of Agronomic Management and Climate on Leaf Phenolic Profiles, Disease Severity, and Grain Yield in Organic and Conventional Wheat Production Systems.

Agricultural intensification over the last 40 years has increased cereal yields, but there is very limited information on the effects of intensification practices (e.g., nondiverse rotations, mineral NPK fertilizer, and pesticides) on crop health and quality. Results from the study reported here suggest that the use of mineral NPK fertilizers reduces phenolic acid and flavonoid concentrations in leaves and increases the susceptibility of wheat to lodging and powdery mildew, when compared to composted FYM inputs. In contrast, the use of herbicides, fungicides, and growth regulators reduces lodging and foliar disease severity but had no effect on phenolic acid and flavonoid concentrations. The use of composted FYM inputs also resulted in a significant grain yield reduction and not substantially reduced the severity of opportunistic pathogens such as Septoria, which remain a major yield limiting factor unless fungicides are used and/or more Septoria resistant varieties become available.

Real-World Data on Health-Related Quality of Life Assessment in Patients With Breast Cancer Receiving Subcutaneous Trastuzumab.

PURPOSE: Trastuzumab, a humanized anti-human epidermal growth factor receptor 2 (anti-HER2) antibody delivered intravenously, has revolutionized the treatment of patients with breast cancer overexpressing HER2 protein. Recently, a newer subcutaneous formulation was shown to have comparable efficacy to the initial intravenous trastuzumab. In this study, we aimed to evaluate the impact of subcutaneous trastuzumab on the health-related quality of life (HRQoL) of patients diagnosed with early or metastatic HER2-overexpressing breast cancer. METHODS: Patients were provided with the EORTC QLQ-C30 (European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Core 30) and the BR-23 questionnaires. The scoring of questionnaires and patient's sociodemographic and clinicopathologic characteristics were recorded and analyzed by descriptive and correlation statistics employing t test and 2-way analysis of variance. RESULTS: A total of 163 patients agreed to participate in the study. About 90 of 163 patients (55.21%) received subcutaneous trastuzumab and 21 patients intravenous trastuzumab (12.88%). A control group of 52 HER2+ patients received chemotherapy without trastuzumab (31.90%). Patients receiving subcutaneous trastuzumab were older and of more advanced disease stage compared with those receiving chemotherapy (58.5 vs 51 years, 39.8% vs 28.8% advanced disease). In univariate analysis, subcutaneous trastuzumab was associated with less nausea and vomiting (P = .002) but worse cognitive function (P = .013) and dyspnea (P = .042). Patients who have received >8 cycles of subcutaneous trastuzumab reported less diarrhea (P = .049) and systemic therapy side effects (P = .015). Multivariate analysis showed that patients without comorbidity receiving subcutaneous trastuzumab had less treatment side effects, less upset by hair loss, and higher emotional functioning. Of note, mastectomy and subcutaneous trastuzumab were associated with improved role functioning (P = .021). In metastatic disease, no negative impact of subcutaneous trastuzumab on HRQoL was found. CONCLUSIONS: The administration of subcutaneous trastuzumab improved certain symptoms and did not adversely affect most of the assessed functional scales. Particularly, in the metastatic setting, subcutaneous trastuzumab had no negative impact on HRQoL.

Alterations of p11 in brain tissue and peripheral blood leukocytes in Parkinson's disease.

Individuals with Parkinson's disease (PD) often suffer from comorbid depression. P11 (S100A10), a member of the S100 family of proteins, is expressed widely throughout the body and is involved in major depressive disorder and antidepressant response. Central p11 levels are reduced in postmortem tissue from depressed individuals; however, p11 has not yet been investigated in PD patients with depression or those without depression. We investigated p11 levels in postmortem PD brains and assessed whether peripheral p11 levels correlate with disease severity. Substantia nigra, putamen, and cortical p11 protein levels were assessed in postmortem brain samples from PD patients and matched controls. In a different set of postmortem brains, p11 mRNA expression was measured in dopaminergic cells from the substantia nigra. Both p11 protein and mRNA levels were decreased in PD patients. Peripheral p11 protein levels were investigated in distinct leukocyte populations from PD patients with depression and those without depression. Monocyte, natural killer (NK) cell, and cytotoxic T-cell p11 levels were positively associated with the severity of PD, and NK cell p11 levels were positively associated with depression scores. Given that inflammation plays a role in both PD and depression, it is intriguing that peripheral p11 levels are altered in immune cells in both conditions. Our data provide insight into the pathological alterations occurring centrally and peripherally in PD. Moreover, if replicated in other cohorts, p11 could be an easily accessible biomarker for monitoring the severity of PD, especially in the context of comorbid depression.

Single-Cell Analysis Reveals a Close Relationship between Differentiating Dopamine and Subthalamic Nucleus Neuronal Lineages.

Stem cell engineering and grafting of mesencephalic dopamine (mesDA) neurons is a promising strategy for brain repair in Parkinson's disease (PD). Refinement of differentiation protocols to optimize this approach will require deeper understanding of mesDA neuron development. Here, we studied this process using transcriptome-wide single-cell RNA sequencing of mouse neural progenitors expressing the mesDA neuron determinant Lmx1a. This approach resolved the differentiation of mesDA and neighboring neuronal lineages and revealed a remarkably close relationship between developing mesDA and subthalamic nucleus (STN) neurons, while also highlighting a distinct transcription factor set that can distinguish between them. While previous hESC mesDA differentiation protocols have relied on markers that are shared between the two lineages, we found that application of these highlighted markers can help to refine current stem cell engineering protocols, increasing the proportion of appropriately patterned mesDA progenitors. Our results, therefore, have important implications for cell replacement therapy in PD.

Nurr1 and Retinoid X Receptor Ligands Stimulate Ret Signaling in Dopamine Neurons and Can Alleviate α-Synuclein Disrupted Gene Expression.

α-synuclein, a protein enriched in Lewy bodies and highly implicated in neurotoxicity in Parkinson's disease, is distributed both at nerve terminals and in the cell nucleus. Here we show that a nuclear derivative of α-synuclein induces more pronounced changes at the gene expression level in mouse primary dopamine (DA) neurons compared to a derivative that is excluded from the nucleus. Moreover, by RNA sequencing we analyzed the extent of genome-wide effects on gene expression resulting from expression of human α-synuclein in primary mouse DA neurons. The results implicated the transcription factor Nurr1 as a key dysregulated target of α-synuclein toxicity. Forced Nurr1 expression restored the expression of hundreds of dysregulated genes in primary DA neurons expressing α-synuclein, and therefore prompted us to test the possibility that Nurr1 can be pharmacologically targeted by bexarotene, a ligand for the retinoid X receptor that forms heterodimers with Nurr1. Although our data demonstrated that bexarotene was ineffective in neuroprotection in rats in vivo, the results revealed that bexarotene has the capacity to coregulate subsets of Nurr1 target genes including the receptor tyrosine kinase subunit Ret. Moreover, bexarotene was able to restore dysfunctional Ret-dependent neurotrophic signaling in α-synuclein-overexpressing mouse DA neurons. These data highlight the role of the Nurr1-Ret signaling pathway as a target of α-synuclein toxicity and suggest that retinoid X receptor ligands with appropriate pharmacological properties could have therapeutic potential in Parkinson's disease. SIGNIFICANCE STATEMENT: How α-synuclein, a protein enriched in Lewy bodies in Parkinson's disease, is causing neuropathology in dopamine neurons remains unclear. This study elucidated how α-synuclein is influencing gene expression and how Nurr1, a transcription factor known to protect dopamine neurons against α-synuclein toxicity, can counteract these effects. Moreover, given the protective role of Nurr1, this study also investigated how Nurr1 could be pharmacologically targeted via bexarotene, a ligand of Nurr1's heterodimerization partner retinoid X receptor (RXR). The results showed that RXR ligands could increase neurotrophic signaling, but provided a mixed picture of its potential in a Parkinson's disease rat model in vivo. However, this study clearly emphasized Nurr1's neuroprotective role and indicated that other RXR ligands could have therapeutic potential in Parkinson's disease.

Dopaminergic control of autophagic-lysosomal function implicates Lmx1b in Parkinson's disease.

The role of developmental transcription factors in maintenance of neuronal properties and in disease remains poorly understood. Lmx1a and Lmx1b are key transcription factors required for the early specification of ventral midbrain dopamine (mDA) neurons. Here we show that conditional ablation of Lmx1a and Lmx1b after mDA neuron specification resulted in abnormalities that show striking resemblance to early cellular abnormalities seen in Parkinson's disease. We found that Lmx1b was required for the normal execution of the autophagic-lysosomal pathway and for the integrity of dopaminergic nerve terminals and long-term mDA neuronal survival. Notably, human LMX1B expression was decreased in mDA neurons in brain tissue affected by Parkinson's disease. Thus, these results reveal a sustained and essential requirement of Lmx1b for the function of midbrain mDA neurons and suggest that its dysfunction is associated with Parkinson's disease pathogenesis.

Sox6 and Otx2 control the specification of substantia nigra and ventral tegmental area dopamine neurons.

Distinct midbrain dopamine (mDA) neuron subtypes are found in the substantia nigra pars compacta (SNc) and the ventral tegmental area (VTA), but it is mainly SNc neurons that degenerate in Parkinson's disease. Interest in how mDA neurons develop has been stimulated by the potential use of stem cells in therapy or disease modeling. However, very little is known about how specific dopaminergic subtypes are generated. Here, we show that the expression profiles of the transcription factors Sox6, Otx2, and Nolz1 define subpopulations of mDA neurons already at the neural progenitor cell stage. After cell-cycle exit, Sox6 selectively localizes to SNc neurons, while Otx2 and Nolz1 are expressed in a subset of VTA neurons. Importantly, Sox6 ablation leads to decreased expression of SNc markers and a corresponding increase in VTA markers, while Otx2 ablation has the opposite effect. Moreover, deletion of Sox6 affects striatal innervation and dopamine levels. We also find reduced Sox6 levels in Parkinson's disease patients. These findings identify Sox6 as a determinant of SNc neuron development and should facilitate the engineering of relevant mDA neurons for cell therapy and disease modeling.