Historically, rabies is the most popular viral brain infection and caused by various Lyssavirus species that are transmitted by dog bites in approximately 99% of human cases 12. ...JC virus (JCV), a ...polyomavirus that commonly establishes asymptomatic infection in the general population, is responsible for progressive multifocal leukoencephalopathy (PML), a fatal demyelinating disease of the CNS, in patients with severe immune deficiency. Fungal infections Unlike bacteria, fungi are eukaryotic (mostly saprophytic) organisms with membrane-bound nuclei that obtain nutrients from organic matter. Aspergillosis and mucormycosis are relatively rare but devastating in immunosuppressed patients, while cerebral phaeohyphomycoses mainly occur in immunocompetent individuals 16. Besides immunological disorders, some environmental, iatrogenic, and host-related factors may predispose an individual to the fungal CNS infection.
Neurotoxicity of Insecticides Cassereau, Julien; Ferré, Marc; Chevrollier, Arnaud ...
Current medicinal chemistry,
08/2017, Letnik:
24, Številka:
27
Journal Article
Recenzirano
Human exposure to insecticides raises serious public health concerns worldwide. Insecticides constitute a wide-ranging heterogeneous group of chemicals, most of which target the nervous system and ...disrupt neurometabolism and/or neurotransmission. Although the acute effects of insecticide poisoning in humans are well documented, the chronic and long-term effects remain difficult to investigate.
We sought to review the present state-of-knowledge of acute, chronic, neurodevelopmental and neurological consequences of human exposure to insecticides.
Animal and epidemiologic studies indicate cognitive, behavioral and psychomotor alterations in mammals chronically exposed to insecticides. Parkinson's and Alzheimer's diseases, amyotrophic lateral sclerosis, and depression, have been regularly associated with insecticide exposure. Clinical studies, supported by experiments on animal models, demonstrate the neurotoxic impact of insecticide exposure during the period of cerebral development, the developing brain being particularly vulnerable to the action of insecticides. Moreover, detoxifying systems that are highly polymorph lead to great inter-individual variability in susceptibility to the neurotoxic effects of insecticides.
Studies on mild chronic exposure to insecticides suggest significant involvement in the pathogenesis of multifactorial neurological diseases. However, the tardive appearance of neurodegenerative disorders and the large variability of inter-individual susceptibility to neurotoxicants make it difficult to assess the relative contribution of insecticide exposure. Close vigilance should therefore be exercised with regard to possible exposure to insecticides, particularly during the period of cerebral development.
Diseases caused by defects in mitochondrial DNA (mtDNA) maintenance machinery, leading to mtDNA deletions, form a specific group of disorders. However, mtDNA deletions also appear during aging, ...interfering with those resulting from mitochondrial disorders.
Here, using next-generation sequencing (NGS) data processed by eKLIPse and data mining, we established criteria distinguishing age-related mtDNA rearrangements from those due to mtDNA maintenance defects. MtDNA deletion profiles from muscle and urine patient samples carrying pathogenic variants in nuclear genes involved in mtDNA maintenance (n = 40) were compared with age-matched controls (n = 90). Seventeen additional patient samples were used to validate the data mining model.
Overall, deletion number, heteroplasmy level, deletion locations, and the presence of repeats at deletion breakpoints were significantly different between patients and controls, especially in muscle samples. The deletion number was significantly relevant in adults, while breakpoint repeat lengths surrounding deletions were discriminant in young subjects.
Altogether, eKLIPse analysis is a powerful tool for measuring the accumulation of mtDNA deletions between patients of different ages, as well as in prioritizing novel variants in genes involved in mtDNA stability.
ABSTRACT
Introduction: There is uncertainty as to whether the Guillain‐Barré syndrome (GBS) subtypes, acute inflammatory demyelinating polyradiculoneuropathy (AIDP) and acute motor axonal neuropathy ...(AMAN), can be diagnosed electrophysiologically. Methods: We prospectively included 58 GBS patients. Electrodiagnostic testing (EDX) was performed at means of 5 and 33 days after disease onset. Two traditional and one recent criteria sets were used to classify studies as demyelinating or axonal. Results were correlated with anti‐ganglioside antibodies and reversible conduction failure (RCF). Results: No classification shifts were observed, but more patients were classified as axonal with recent criteria. RCF and anti‐ganglioside antibodies were present in both subtypes, more frequently in the axonal subtype. Discussion: Serial EDX has no effect on GBS subtype proportions. The absence of exclusive correlation with RCF and anti‐ganglioside antibodies may challenge the concept of demyelinating and axonal GBS subtypes based upon electrophysiological criteria. Frequent RCF indicates that nodal/paranodal alterations may represent the main pathophysiology. Muscle Nerve 58: 23–28, 2018.
Mitochondrial dynamics is a process that balances fusion and fission events, the latter providing a mechanism for segregating dysfunctional mitochondria. Fission is controlled by the mitochondrial ...membrane potential (ΔΨm), optic atrophy 1 (OPA1) cleavage, and DRP1 recruitment. It is thought that this process is closely linked to the activity of the mitochondrial respiratory chain (MRC). However, we report here that MRC inhibition does not decrease ΔΨm nor increase fission, as evidenced by hyperconnected mitochondria. Conversely, blocking F0F1-ATP synthase activity induces fragmentation. We show that the F0F1-ATP synthase is sensing the inhibition of MRC activity by immediately promoting its reverse mode of action to hydrolyze matrix ATP and restoring ΔΨm, thus preventing fission. While this reverse mode is expected to be inhibited by the ATPase inhibitor ATPIF1, we show that this sensing is independent of this factor. We have unraveled an unexpected role of F0F1-ATP synthase in controlling the induction of fission by sensing and maintaining ΔΨm.
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•Defects in the respiratory chain do not lead to fragmentation of mitochondria•ATP hydrolysis by F0F1-ATP synthase ensures connectivity of mitochondrial network•Mitochondrial fission resistance relies on glycolytic energetic metabolism•F0F1-ATP synthase mutants are prone to MRC-induced mitochondrial fission
Biochemistry; Cell biology; Functional aspects of cell biology
Leber's hereditary optic neuropathy (LHON) is caused by mutations in the complex I subunits of the respiratory chain. Although patients have been treated with idebenone since 1992, the efficacy of ...the drug is still a matter of debate.
We evaluated the effect of idebenone in fibroblasts from LHON patients using enzymatic and polarographic measurements.
Complex I activity was 42% greater in treated fibroblasts compared to controls (p = 0.002). Despite this complex I activity improvement, the effects on mitochondrial respiration were contradictory, leading to impairment in some cases and stimulation in others.
These results indicate that idebenone is able to compensate the complex I deficiency in LHON patient cells with variable effects on respiration, indicating that the patients might not be equally likely to benefit from the treatment.
Hereditary spastic paraplegia refers to a genetically heterogeneous syndrome. We identified five members of a family suffering from a late-onset spastic paraplegia-like disorder, carrying the ...homoplasmic m.9176 T>C mutation in the mitochondrial ATP6 gene. The clinical severity of the disease observed in the family was correlated with the biochemical and assembly defects of the ATP synthase. The m.9176 T>C mutation has been previously associated to Leigh syndrome or familial bilateral striatal necrosis. Other factors such as modifying genes may be involved in the phenotypic expression of the disease. The family belongs to the mitochondrial haplogroup J, previously shown to play a role in modulating the phenotype of mitochondrial diseases and be associated with longevity. Moreover other nuclear modifying genes or environmental factors may contribute to the disease phenotype. This finding extends the genetic heterogeneity of the hereditary spastic paraplegia together with the clinical spectrum of mutations of the ATP6 gene.
The ganglioside-induced differentiation-associated protein 1 gene (GDAP1), which is involved in the Charcot-Marie-Tooth disease (CMT), the most commonly inherited peripheral neuropathy, encodes a ...protein anchored to the mitochondrial outer membrane. The phenotypic presentations of patients carrying GDAP1 mutations are heterogeneous, making it difficult to determine genotype-phenotype correlations, since the majority of the mutations have been found in only a few unrelated patients. Locus-specific databases (LSDB) established in the framework of the Human Variome Project provide powerful tools for the investigation of such rare diseases.
We report the development of a publicly accessible LSDB for the GDAP1 gene. The GDAP1 LSDB has adopted the Leiden Open-source Variation Database (LOVD) software platform. This database, which now contains 57 unique variants reported in 179 cases of CMT, offers a detailed description of the molecular, clinical and electrophysiological data of the patients. The usefulness of the GDAP1 database is illustrated by the finding that GDAP1 mutations lead to primary axonal damage in CMT, with secondary demyelination in the more severe cases of the disease.
Findings of this nature should lead to a better understanding of the pathophysiology of CMT. Finally, the GDAP1 LSDB, which is part of the mitodyn.org portal of databases of genes incriminated in disorders involving mitochondrial dynamics and bioenergetics, should yield new insights into mitochondrial diseases.
Mohassel et al. provide unprecedented dichotomy of consequences on sphingolipid biosynthesis between pathogenic variants in the SPTLC1 gene, responsible for either amyotrophic lateral sclerosis (ALS) ...or hereditary sensory and autonomic neuropathy type 1 (HSAN1). Normalization of sphingolipid levels by siRNA selectively targeting the ALS mutant allele mRNA sheds light on new therapeutic approaches.
Engineered Microbes for Producing Anticholinergics Courdavault, Vincent; Cassereau, Julien; Papon, Nicolas
Chembiochem : a European journal of chemical biology,
April 16, 2021, Letnik:
22, Številka:
8
Journal Article
Recenzirano
The tropane alkaloids (TAs) hyoscyamine and scopolamine function as acetylcholine receptor antagonists and are used clinically as parasympatholytics to treat neuromuscular disorders in humans. While ...TAs are synthesized in a small subset of plant families, these specialized metabolites are only accumulated in limited quantities in plant organs. The complex chemical structures of these compounds make their industrial production by chemical synthesis very challenging, Therefore, the supply of these TAs still relies on intensive farming of Duboisia shrubs in tropical countries. Many adverse factors such as climate fluctuations and pandemics can thus influence annual world production. Based on the landmark microbial production of the antimalarial semi‐synthetic artemisinin, the Smolke group recently developed a yeast cell factory capable of de novo synthesizing hyoscyamine and scopolamine, thus paving the way for an alternative production of these compounds.
The Smolke group recently developed yeast strains producing the tropane alkaloids scopolamine and hyoscyamine to enable a possible alternative supply of these compounds by metabolic engineering. Such a tour‐de‐force notably required the identification of a missing enzyme of the pathway, invalidation of yeast endogenous genes and relocation of enzymes to restore a synthesis activity.
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