H63D variant of the homeostatic iron regulator (HFE) gene alters α-synuclein expression, aggregation, and toxicity.

Pathological features of Parkinson's disease include the formation of Lewy bodies containing α-synuclein and the accumulation of iron in the substantia nigra. Previous studies have suggested that iron accumulation contributes to the Parkinson's disease pathology through reactive oxygen species production and accelerated α-synuclein aggregation. This study examines the effects of commonly occurring H63D variant of the homeostatic iron regulatory (HFE) gene on α-synuclein pathology in cell culture and animal models. H63D HFE expression in SH-SY5Y cells lowered endogenous α-synuclein levels and significantly decreased pre-formed fibril-induced α-synuclein aggregation. H63D HFE cells were also protected from pre-formed fibril-induced apoptosis. Autophagic flux, a major pathway for α-synuclein clearance, was increased in H63D HFE cells. Expression of REDD1 was elevated and rapamycin treatment was unable to further induce autophagy, indicating mTORC1 inhibition as the main mechanism of autophagy induction. Moreover, siRNA knockdown of REDD1 in H63D HFE cells decreased autophagic flux and increased the sensitivity to PFF-mediated toxicity. While iron chelator (deferiprone) treatment rescued WT HFE cells from pre-formed fibril toxicity, it exacerbated or was unable to rescue H63D HFE cells. In the in vivo pre-formed fibril intracranial injection model, H67D Hfe (mouse homolog of the human H63D HFE variant) C57BL/6J × 129 mice showed less α-synuclein aggregation and less decline in motor function compared to WT Hfe. Collectively, this study suggests that H63D HFE variant modifies α-synuclein pathology through the induction of autophagy and has the potential to impact the pathogenesis and treatment response in Parkinson's disease.

Persistent Hemichorea and Caudate Atrophy in Untreated Diabetic Striatopathy: A Case Report.

BACKGROUND: Neurological complications of diabetes and hyperglycemia are relatively common but the specific manifestations can vary widely. Diabetic striatal disease or "diabetic striatopathy" is an uncommon condition usually thought to result from hyperglycemic injury to the basal ganglia, producing a hyperkinetic movement disorder, usually choreiform in nature. Symptoms are generally reversible with treatment of the hyperglycemia. CASE DESCRIPTION: We report the case of a 57-year-old woman presenting with a unilateral choreoathetosis of the left upper extremity, persistent for 4 years. Contemporaneous imaging demonstrated severe atrophy of the right caudate nucleus, while imaging obtained at the onset of symptoms was consistent with a right diabetic striatopathy. Symptoms improved with the use of dopamine antagonists and benzodiazepines. CONCLUSION: Although generally considered to be fully reversible, this case demonstrates that diabetic striatopathy can result in permanent structural lesions with persistent symptoms if left untreated.

Neurotoxicity of the Parkinson Disease-Associated Pesticide Ziram Is Synuclein-Dependent in Zebrafish Embryos.

BACKGROUND: Exposure to the commonly used dithiocarbamate (DTC) pesticides is associated with an increased risk of developing Parkinson disease (PD), although the mechanisms by which they exert their toxicity are not completely understood. OBJECTIVE: We studied the mechanisms of ziram's (a DTC fungicide) neurotoxicity in vivo. METHODS: Zebrafish (ZF) embryos were utilized to determine ziram's effects on behavior, neuronal toxicity, and the role of synuclein in its toxicity. RESULTS: Nanomolar-range concentrations of ziram caused selective loss of dopaminergic (DA) neurons and impaired swimming behavior. Because ziram increases α-synuclein (α-syn) concentrations in rat primary neuronal cultures, we investigated the effect of ziram on ZF γ-synuclein 1 (γ1). ZF express 3 synuclein isoforms, and ZF γ1 appears to be the closest functional homologue to α-syn. We found that recombinant ZF γ1 formed fibrils in vitro, and overexpression of ZF γ1 in ZF embryos led to the formation of neuronal aggregates and neurotoxicity in a manner similar to that of α-syn. Importantly, knockdown of ZF γ1 with morpholinos and disruption of oligomers with the molecular tweezer CLR01 prevented ziram's DA toxicity. CONCLUSIONS: These data show that ziram is selectively toxic to DA neurons in vivo, and this toxicity is synuclein-dependent. These findings have important implications for understanding the mechanisms by which pesticides may cause PD. Citation: Lulla A, Barnhill L, Bitan G, Ivanova MI, Nguyen B, O'Donnell K, Stahl MC, Yamashiro C, Klärner FG, Schrader T, Sagasti A, Bronstein JM. 2016. Neurotoxicity of the Parkinson disease-associated pesticide ziram is synuclein-dependent in zebrafish embryos. Environ Health Perspect 124:1766-1775; http://dx.doi.org/10.1289/EHP141.

Stinging insect identification: Are the allergy specialists any better than their patients?

BACKGROUND: It has been reported that the general population is not skillful at identifying stinging insects with the exception of the honeybee. No information is available to evaluate allergy physicians' accuracy with stinging insect identification. OBJECTIVE: To measure the accuracy of allergists' ability to identify stinging insects and assess their common practices for evaluating individuals with suspected insect hypersensitivity. METHODS: A picture-based survey and a dried specimen insect box were constructed to determine allergists' and nonallergists' accuracy in identifying insects. Allergists attending the 2013 American College of Allergy, Asthma, and Immunology meeting were invited to participate in the study. Common practice approaches for evaluating individuals with stinging insect hypersensitivity were also investigated using a brief questionnaire. RESULTS: Allergy physicians are collectively better at insect identification than nonallergists. Overall, the mean (SD) number of correct responses for nonallergists was 5.4 (2.0) of a total of 10. This score was significantly lower than the score for allergists (6.1 [2.0]; P = .01) who participated in the study. Most allergists (78.5%) test for all stinging insects and use skin testing (69.5%) as the initial test of choice for evaluating individuals with insect hypersensitivity. CONCLUSION: Overall, allergists are more skilled at Hymenoptera identification. Most allergy specialists reported testing for all stinging insects when evaluating insect hypersensitivity, and skin testing was the preferred testing method in nearly 70% of allergists. These data support the practice parameter's recommendation to consider testing for all flying Hymenoptera insects during venom evaluation, which most of the participating allergists surveyed incorporate into their clinical practice.

Capgras Syndrome in a Patient with Parkinson's Disease after Bilateral Subthalamic Nucleus Deep Brain Stimulation: A Case Report.

Capgras syndrome is a delusional misidentification syndrome (DMS) which can be seen in neurodegenerative diseases such as Lewy body dementia and, to a lesser extent, in Parkinson's disease (PD). Here, we report the case of a 78-year-old man with a history of idiopathic PD who developed Capgras syndrome following bilateral subthalamic nucleus deep brain stimulation (DBS) implantation. As the risk of DMS has been related to deficits in executive, memory, and visuospatial function preoperatively, this case highlights the importance of continuing to improve patient selection for DBS surgery. Capgras syndrome is a rare potential complication of DBS surgery in PD patients with preexisting cognitive decline.

Recurrent Episodes of Stroke-Like Symptoms in a Patient with Charcot-Marie-Tooth Neuropathy X Type 1.

Charcot-Marie-Tooth disease (CMT), also known as hereditary motor sensory neuropathy, is a heterogeneous group of disorders best known for causing inherited forms of peripheral neuropathy. The X-linked form, CMTX1, is caused by mutations in the gap junction protein beta 1 (GJB1) gene, expressed both by peripheral Schwann cells and central oligodendrocytes. Central manifestations are known but are rare, and there are few case reports of leukoencephalopathy with transient or persistent neurological deficits in patients with this CMT subtype. Here, we report the case of a man with multiple male and female family members affected by neuropathy who carries a pathologic mutation in GJB1. He has experienced three transient episodes with variable neurological deficits over the course of 7 years with corresponding changes on magnetic resonance imaging (MRI). This case illustrates CMT1X as a rare cause of transient neurological deficit and demonstrates the evolution of associated reversible abnormalities on MRI over time. To the best of our knowledge, this report provides the longest period of serial imaging in a single patient with this condition in the English language literature.

The HIT study: Hymenoptera Identification Test--how accurate are people at identifying stinging insects?

BACKGROUND: Stinging insects in the order Hymenoptera include bees, wasps, yellow jackets, hornets, and ants. Hymenoptera sting injuries range from localized swelling to rarely death. Insect identification is helpful in the management of sting injuries. OBJECTIVE: To determine the accuracy of adults in identifying stinging insects and 2 insect nests. METHODS: This was a cross-sectional, multicenter study using a picture-based survey to evaluate an individual's success at identifying honeybees, wasps, bald-face hornets, and yellow jackets. Bald-face hornet and paper wasp nest identification also was assessed in this study. RESULTS: Six hundred forty participants completed the questionnaire. Overall, the mean number of correct responses was 3.2 (SD 1.3) of 6. Twenty participants (3.1%) correctly identified all 6 stinging insects and nests and only 10 (1.6%) were unable to identify any of the pictures correctly. The honeybee was the most accurately identified insect (91.3%) and the paper wasp was the least correctly identified insect (50.9%). For the 6 questions regarding whether the participant had been stung in the past by any of the insects (including an unidentified insect), 91% reported being stung by at least 1. Men were more successful at identify stinging insects correctly (P = .002), as were participants stung by at least 4 insects (P = .018). CONCLUSION: This study supports the general perception that adults are poor discriminators in distinguishing stinging insects and nests with the exception of the honeybee. Men and those participants who reported multiple stings to at least 4 insects were more accurate overall in insect identification.

Axon degeneration and PGC-1α-mediated protection in a zebrafish model of α-synuclein toxicity.

α-synuclein (aSyn) expression is implicated in neurodegenerative processes, including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). In animal models of these diseases, axon pathology often precedes cell death, raising the question of whether aSyn has compartment-specific toxic effects that could require early and/or independent therapeutic intervention. The relevance of axonal pathology to degeneration can only be addressed through longitudinal, in vivo monitoring of different neuronal compartments. With current imaging methods, dopaminergic neurons do not readily lend themselves to such a task in any vertebrate system. We therefore expressed human wild-type aSyn in zebrafish peripheral sensory neurons, which project elaborate superficial axons that can be continuously imaged in vivo. Axonal outgrowth was normal in these neurons but, by 2 days post-fertilization (dpf), many aSyn-expressing axons became dystrophic, with focal varicosities or diffuse beading. Approximately 20% of aSyn-expressing cells died by 3 dpf. Time-lapse imaging revealed that focal axonal swelling, but not overt fragmentation, usually preceded cell death. Co-expressing aSyn with a mitochondrial reporter revealed deficits in mitochondrial transport and morphology even when axons appeared overtly normal. The axon-protective protein Wallerian degeneration slow (WldS) delayed axon degeneration but not cell death caused by aSyn. By contrast, the transcriptional coactivator PGC-1α, which has roles in the regulation of mitochondrial biogenesis and reactive-oxygen-species detoxification, abrogated aSyn toxicity in both the axon and the cell body. The rapid onset of axonal pathology in this system, and the relatively moderate degree of cell death, provide a new model for the study of aSyn toxicity and protection. Moreover, the accessibility of peripheral sensory axons will allow effects of aSyn to be studied in different neuronal compartments and might have utility in screening for novel disease-modifying compounds.

Aldehyde dehydrogenase inhibition as a pathogenic mechanism in Parkinson disease.

Parkinson disease (PD) is a neurodegenerative disorder particularly characterized by the loss of dopaminergic neurons in the substantia nigra. Pesticide exposure has been associated with PD occurrence, and we previously reported that the fungicide benomyl interferes with several cellular processes potentially relevant to PD pathogenesis. Here we propose that benomyl, via its bioactivated thiocarbamate sulfoxide metabolite, inhibits aldehyde dehydrogenase (ALDH), leading to accumulation of the reactive dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL), preferential degeneration of dopaminergic neurons, and development of PD. This hypothesis is supported by multiple lines of evidence. (i) We previously showed in mice the metabolism of benomyl to S-methyl N-butylthiocarbamate sulfoxide, which inhibits ALDH at nanomolar levels. We report here that benomyl exposure in primary mesencephalic neurons (ii) inhibits ALDH and (iii) alters dopamine homeostasis. It induces selective dopaminergic neuronal damage (iv) in vitro in primary mesencephalic cultures and (v) in vivo in a zebrafish system. (vi) In vitro cell loss was attenuated by reducing DOPAL formation. (vii) In our epidemiology study, higher exposure to benomyl was associated with increased PD risk. This ALDH model for PD etiology may help explain the selective vulnerability of dopaminergic neurons in PD and provide a potential mechanism through which environmental toxicants contribute to PD pathogenesis.

Potential therapies for peanut allergy.

OBJECTIVE: To review the investigated therapies for peanut allergy beyond avoidance measures and self-injectable epinephrine. DATA SOURCES: A PubMed search was performed using the Keywords peanut allergy and therapy. Additional citations were generated by surveying the reference lists of the pulled articles STUDY SELECTION: More than 120 articles were reviewed and references were selected based on their relevance to the subject matter. RESULTS: Peanut allergy affects more than 1% of the US population and is increasing in prevalence. During the past 15 years multiple therapies have been researched and many have provided promising results. Sustained oral tolerance over desensitization is the goal, and most therapies are unable to demonstrate this because they are currently in their relative infancy. Therapeutic options should be safe, easily administered, and relatively inexpensive. To minimize risk, many therapies will require investigation of combined modalities. CONCLUSIONS: Peanut allergy is a challenging diagnosis for physicians because few treatment options are available. However, it seems plausible that new offerings may become accepted therapy within the next decade. The ability of a patient to tolerate amounts of peanut in an unintentional ingestion without experiencing anaphylaxis would offer peace of mind to patients and families living with peanut allergy.

O-fucosylation of muscle agrin determines its ability to cluster acetylcholine receptors.

Protein O-fucosyltransferase 1 (Pofut1) transfers fucose to serine or threonine on proteins, including Notch receptors, that contain EGF repeats with a particular consensus sequence. Here we demonstrate that agrin is O-fucosylated in a Pofut1-dependent manner, and that this glycosylation can regulate agrin function. Fucosylation of recombinant C45 agrin, both active (neural, z8) and inactive (muscle, z0) splice forms, was eliminated when agrin was overexpressed in Pofut1-deficient cells or by mutation of a consensus site for Pofut1 fucosylation (serine 1726 in the EGF4 domain). Loss of O-fucosylation caused a gain of function for muscle agrin such that it stimulated AChR clustering and MuSK phosphorylation in cultured myotubes at levels normally only found with the neural splice form. Deletion of Pofut1 in cultured primary myotubes and in adult skeletal muscle increased AChR aggregation. In addition, Pofut1 gene and protein expression and Pofut1 activity of the EGF4 domain of agrin were modulated during neuromuscular development. These data are consistent with a role for Pofut1 in AChR aggregation during synaptogenesis via the regulation of the synaptogenic activity of muscle agrin.