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1.
Ann Neurol ; 2024 Jul 01.
Article in English | MEDLINE | ID: mdl-38949221

ABSTRACT

OBJECTIVE: Alice in Wonderland syndrome (AIWS) profoundly affects human perception of size and scale, particularly regarding one's own body and the environment. Its neuroanatomical basis has remained elusive, partly because brain lesions causing AIWS can occur in different brain regions. Here, we aimed to determine if brain lesions causing AIWS map to a distributed brain network. METHODS: A retrospective case-control study analyzing 37 cases of lesion-induced AIWS identified through systematic literature review was conducted. Using resting-state functional connectome data from 1,000 healthy individuals, the whole-brain connections of each lesion were estimated and contrasted with those from a control dataset comprising 1,073 lesions associated with 25 other neuropsychiatric syndromes. Additionally, connectivity findings from lesion-induced AIWS cases were compared with functional neuroimaging results from 5 non-lesional AIWS cases. RESULTS: AIWS-associated lesions were located in various brain regions with minimal overlap (≤33%). However, the majority of lesions (≥85%) demonstrated shared connectivity to the right extrastriate body area, known to be selectively activated by viewing body part images, and the inferior parietal cortex, involved in size and scale judgements. This pattern was uniquely characteristic of AIWS when compared with other neuropsychiatric disorders (family-wise error-corrected p < 0.05) and consistent with functional neuroimaging observations in AIWS due to nonlesional causes (median correlation r = 0.56, interquartile range 0.24). INTERPRETATION: AIWS-related perceptual distortions map to one common brain network, encompassing regions critical for body representation and size-scale processing. These findings lend insight into the neuroanatomical localization of higher-order perceptual functions, and may inform future therapeutic strategies for perceptual disorders. ANN NEUROL 2024.

2.
Neurology ; 101(15): e1483-e1494, 2023 10 10.
Article in English | MEDLINE | ID: mdl-37596042

ABSTRACT

BACKGROUND AND OBJECTIVES: The cerebello-thalamo-cortical circuit plays a critical role in essential tremor (ET). However, abnormalities have been reported in multiple brain regions outside this circuit, leading to inconsistent characterization of ET pathophysiology. Here, we test whether these mixed findings in ET localize to a common functional network and whether this network has therapeutic relevance. METHODS: We conducted a systematic literature search to identify studies reporting structural or metabolic brain abnormalities in ET. We then used 'coordinate network mapping,' which leverages a normative connectome (n = 1,000) of resting-state fMRI data to identify regions commonly connected to findings across all studies. To assess whether these regions may be relevant for the treatment of ET, we compared our network with a therapeutic network derived from lesions that relieved ET. Finally, we investigated whether the functional connectivity of this ET symptom network is abnormal in an independent cohort of patients with ET as compared with healthy controls. RESULTS: Structural and metabolic brain abnormalities in ET were located in heterogeneous regions throughout the brain. However, these coordinates were connected to a common functional brain network, including the cerebellum, thalamus, motor cortex, precuneus, inferior parietal lobe, and insula. The cerebellum was identified as the hub of this network because it was the only brain region that was both functionally connected to the findings of over 90% of studies and significantly different in connectivity compared with a control data set of other movement disorders. This network was strikingly similar to the therapeutic network derived from lesions improving ET, with key regions aligning in the thalamus and cerebellum. Furthermore, positive functional connectivity between the cerebellar network hub and the sensorimotor cortices was significantly reduced in patients with ET compared with healthy controls, and connectivity within this network was correlated with tremor severity and cognitive functioning. DISCUSSION: These findings suggest that the cerebellum is the central hub of a network commonly connected to structural and metabolic abnormalities in ET. This network may have therapeutic utility in refining and informing new targets for neuromodulation of ET.


Subject(s)
Brain Diseases , Connectome , Essential Tremor , Sensorimotor Cortex , Humans , Brain Diseases/pathology , Brain Mapping , Cerebellum/pathology , Essential Tremor/diagnostic imaging , Magnetic Resonance Imaging , Neural Pathways , Tremor
3.
Brain Commun ; 5(3): fcad172, 2023.
Article in English | MEDLINE | ID: mdl-37324240

ABSTRACT

Parkinsonism is a feature of several neurodegenerative disorders, including Parkinson's disease, progressive supranuclear palsy, corticobasal syndrome and multiple system atrophy. Neuroimaging studies have yielded insights into parkinsonian disorders; however, due to variability in results, the brain regions consistently implicated in these disorders remain to be characterized. The aim of this meta-analysis was to identify consistent brain abnormalities in individual parkinsonian disorders (Parkinson's disease, progressive supranuclear palsy, corticobasal syndrome and multiple system atrophy) and to investigate any shared abnormalities across disorders. A total of 44 591 studies were systematically screened following searches of two databases. A series of whole-brain activation likelihood estimation meta-analyses were performed on 132 neuroimaging studies (69 Parkinson's disease; 23 progressive supranuclear palsy; 17 corticobasal syndrome; and 23 multiple system atrophy) utilizing anatomical MRI, perfusion or metabolism PET and single-photon emission computed tomography. Meta-analyses were performed in each parkinsonian disorder within each imaging modality, as well as across all included disorders. Results in progressive supranuclear palsy and multiple system atrophy aligned with current imaging markers for diagnosis, encompassing the midbrain, and brainstem and putamen, respectively. PET imaging studies of patients with Parkinson's disease most consistently reported abnormality of the middle temporal gyrus. No significant clusters were identified in corticobasal syndrome. When examining abnormalities shared across all four disorders, the caudate was consistently reported in MRI studies, whilst the thalamus, inferior frontal gyrus and middle temporal gyri were commonly implicated by PET. To our knowledge, this is the largest meta-analysis of neuroimaging studies in parkinsonian disorders and the first to characterize brain regions implicated across parkinsonian disorders.

4.
Neurology ; 99(18): e1957-e1967, 2022 11 01.
Article in English | MEDLINE | ID: mdl-35977840

ABSTRACT

BACKGROUND AND OBJECTIVES: Brain lesions are a well-recognized etiology of dystonia. These cases are especially valuable because they offer causal insight into the neuroanatomical substrates of dystonia. To date, knowledge of lesion-induced dystonia comes mainly from isolated case reports or small case series, restricting broader description and analysis. METHODS: Cases of lesion-induced dystonia were first identified from a systematic review of published literature. Latent class analysis then investigated whether patients could be classified into subgroups based on lesion location and body regions affected by dystonia. Regression analyses subsequently investigated whether subgroup membership predicted clinical characteristics of dystonia. RESULTS: Three hundred fifty-nine published cases were included. Lesions causing dystonia occurred in heterogeneous locations, most commonly in the basal ganglia (46.2%), followed by the thalamus (28.1%), brainstem (22.6%), and white matter (21.2%). The most common form of lesion-induced dystonia was focal dystonia (53.2%), with the hand (49.9%) and arm (44.3%) most commonly affected. Of all cases, 86.6% reported co-occurring neurologic manifestations and 26.1% reported other movement disorders. Latent class analysis identified 3 distinct subgroups of patients: those with predominantly limb dystonias, which were associated with basal ganglia lesions; those with hand dystonia, associated with thalamic lesions; and those with predominantly cervical dystonia, associated with brainstem and cerebellar lesions. Regression demonstrated significant differences between these subgroups on a range of dystonia symptoms, including dystonic tremor, symptom latency, other movement disorders, and dystonia variability. DISCUSSION: Although dystonia can be induced by lesions to numerous brain regions, there are distinct relationships between lesion locations and dystonic body parts. This suggests that the affected brain networks are different between types of dystonia.


Subject(s)
Dystonic Disorders , Movement Disorders , Torticollis , Humans , Dystonic Disorders/complications , Basal Ganglia/diagnostic imaging , Basal Ganglia/pathology , Movement Disorders/complications , Brain/diagnostic imaging , Brain/pathology , Torticollis/complications
5.
Biochemistry ; 57(50): 6860-6867, 2018 12 18.
Article in English | MEDLINE | ID: mdl-30452235

ABSTRACT

Aromatic prenylation is an important step in the biosynthesis of many natural products and leads to an astonishing diversity of chemical structures. Cyanobactin pathways frequently encode aromatic prenyltransferases that catalyze the prenylation of these macrocyclic and linear peptides. Here we characterized the anacyclamide ( acy) biosynthetic gene cluster from Anabaena sp. UHCC-0232. Partial reconstitution of the anacyclamide pathway, heterologous expression, and in vitro biochemical characterization demonstrate that the AcyF enzyme, encoded in the acy biosynthetic gene cluster, is a Trp N-prenyltransferase. Bioinformatic analysis suggests the monophyletic origin and rapid diversification of cyanobactin prenyltransferase enzymes and the multiple origins of N-1 Trp prenylation in prenylated natural products. The AcyF enzyme displayed high flexibility toward a range of Trp-containing substrates and represents an interesting new tool for biocatalytic applications.


Subject(s)
Dimethylallyltranstransferase/metabolism , Peptides, Cyclic/biosynthesis , Peptides, Cyclic/chemistry , Amino Acid Sequence , Anabaena/enzymology , Anabaena/genetics , Bacterial Proteins/genetics , Bacterial Proteins/metabolism , Biological Products/chemistry , Biological Products/metabolism , Biosynthetic Pathways , Dimethylallyltranstransferase/genetics , Genes, Bacterial , Multigene Family , Phylogeny , Prenylation , Substrate Specificity , Tryptophan/chemistry
6.
Nucleic Acids Res ; 46(3): 1308-1320, 2018 02 16.
Article in English | MEDLINE | ID: mdl-29228292

ABSTRACT

To establish a prophage state, the genomic DNA of temperate bacteriophages normally becomes integrated into the genome of their host bacterium by integrase-mediated, site-specific DNA recombination. Serine integrases catalyse a single crossover between an attachment site in the host (attB) and a phage attachment site (attP) on the circularized phage genome to generate the integrated prophage DNA flanked by recombinant attachment sites, attL and attR. Exiting the prophage state and entry into the lytic growth cycle requires an additional phage-encoded protein, the recombination directionality factor or RDF, to mediate recombination between attL and attR and excision of the phage genome. The RDF is known to bind integrase and switch its activity from integration (attP x attB) to excision (attL x attR) but its precise mechanism is unclear. Here, we identify amino acid residues in the RDF, gp3, encoded by the Streptomyces phage ϕC31 and within the ϕC31 integrase itself that affect the gp3:Int interaction. We show that residue substitutions in integrase that reduce gp3 binding adversely affect both excision and integration reactions. The mutant integrase phenotypes are consistent with a model in which the RDF binds to a hinge region at the base of the coiled-coil motif in ϕC31 integrase.


Subject(s)
Attachment Sites, Microbiological , DNA, Bacterial/chemistry , DNA-Binding Proteins/chemistry , Integrases/chemistry , Siphoviridae/genetics , Streptomyces/virology , Viral Proteins/chemistry , Amino Acid Sequence , Amino Acid Substitution , Binding Sites , Cloning, Molecular , DNA, Bacterial/genetics , DNA, Bacterial/metabolism , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Escherichia coli/genetics , Escherichia coli/metabolism , Gene Expression , Genetic Vectors/chemistry , Genetic Vectors/metabolism , Integrases/genetics , Integrases/metabolism , Lysogeny , Models, Molecular , Mutation , Protein Binding , Protein Conformation, alpha-Helical , Protein Conformation, beta-Strand , Protein Interaction Domains and Motifs , Recombinant Proteins/chemistry , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Sequence Alignment , Sequence Homology, Amino Acid , Siphoviridae/chemistry , Siphoviridae/metabolism , Streptomyces/chemistry , Thermodynamics , Viral Proteins/genetics , Viral Proteins/metabolism
7.
BMC Biotechnol ; 14: 51, 2014 May 30.
Article in English | MEDLINE | ID: mdl-24885867

ABSTRACT

BACKGROUND: Integrating vectors based on the int/attP loci of temperate phages are convenient and used widely, particularly for cloning genes in Streptomyces spp. RESULTS: We have constructed and tested a novel integrating vector based on g27, encoding integrase, and attP site from the phage, SV1. This plasmid, pBF3 integrates efficiently in S. coelicolor and S. lividans but surprisingly fails to generate stable integrants in S. venezuelae, the natural host for phage SV1. CONCLUSION: pBF3 promises to be a useful addition to the range of integrating vectors currently available for Streptomyces molecular genetics.


Subject(s)
Bacteriophages/genetics , Genetic Vectors/metabolism , Streptomyces/metabolism , Attachment Sites, Microbiological/genetics , Base Sequence , Integrases/chemistry , Integrases/genetics , Integrases/metabolism , Molecular Sequence Data , Sequence Alignment
8.
Mol Microbiol ; 80(6): 1450-63, 2011 Jun.
Article in English | MEDLINE | ID: mdl-21564337

ABSTRACT

The serine integrase, Int, from the Streptomyces phage φC31 mediates the integration and excision of the phage genome into and out of the host chromosome. Integrases usually require a recombination directionality factor (RDF) or Xis to control integration and excision and, as φC31 Int only mediates integration in the absence of other phage proteins, we sought to identify a φC31 RDF. Here we report that the φC31 early protein, gp3 activated attL x attR recombination and inhibited attP x attB recombination. Gp3 binds to Int in solution and when Int is bound to the attachment sites. Kinetic analysis of the excision reaction suggested that gp3 modifies the interactions between Int and the substrates to form an active recombinase. In the presence of gp3, Int assembles an excision synaptic complex and the accumulation of the integration complex is inhibited. The structure of the excision synaptic complex, like that of the hyperactive mutant of Int, IntE449K, appeared to be biased towards one that favours the production of correctly joined products. The functional properties of φC31 gp3 resemble those of the evolutionarily unrelated RDF from phage Bxb1, suggesting that these two RDFs have arisen through convergent evolution.


Subject(s)
Integrases/metabolism , Recombination, Genetic , Streptococcus Phages/metabolism , Viral Proteins/metabolism , Attachment Sites, Microbiological , Escherichia coli/virology , Integrases/genetics , Molecular Sequence Data , Protein Binding , Streptococcus Phages/enzymology , Streptococcus Phages/genetics , Viral Proteins/genetics , Virus Integration
9.
Nucleic Acids Res ; 36(12): 3879-91, 2008 Jul.
Article in English | MEDLINE | ID: mdl-18502775

ABSTRACT

Bacteriophage C31 encodes an integrase, which acts on the phage and host attachment sites, attP and attB, to form an integrated prophage flanked by attL and attR. In the absence of accessory factors, C31 integrase cannot catalyse attL x attR recombination to excise the prophage. To understand the mechanism of directionality, mutant integrases were characterized that were active in excision. A hyperactive integrase, Int E449K, gained the ability to catalyse attL x attR, attL x attL and attR x attR recombination whilst retaining the ability to recombine attP x attB. A catalytically defective derivative of this mutant, Int S12A, E449K, could form stable complexes with attP/attB, attL/attR, attL/attL and attR/attR under conditions where Int S12A only complexed with attP/attB. Further analysis of the Int E449K-attL/attR synaptic events revealed a preference for one of the two predicted synapse structures with different orientations of the attL/attR sites. Several amino acid substitutions conferring hyperactivity, including E449K, were localized to one face of a predicted coiled-coil motif in the C-terminal domain. This work shows that a motif in the C-terminal domain of C31 integrase controls the formation of the synaptic interface in both integration and excision, possibly through a direct role in protein-protein interactions.


Subject(s)
Bacteriophages/enzymology , Integrases/chemistry , Recombination, Genetic , Viral Proteins/chemistry , Amino Acid Motifs , Amino Acid Sequence , Amino Acid Substitution , Attachment Sites, Microbiological , Integrases/genetics , Integrases/metabolism , Molecular Sequence Data , Mutation , Protein Structure, Tertiary , Streptomyces/virology , Viral Proteins/genetics , Viral Proteins/metabolism
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