We report that, in the rat hippocampus, learning leads to a significant increase in extracellular lactate levels that derive from glycogen, an energy reserve selectively localized in astrocytes. ...Astrocytic glycogen breakdown and lactate release are essential for long-term but not short-term memory formation, and for the maintenance of long-term potentiation (LTP) of synaptic strength elicited in vivo. Disrupting the expression of the astrocytic lactate transporters monocarboxylate transporter 4 (MCT4) or MCT1 causes amnesia, which, like LTP impairment, is rescued by L-lactate but not equicaloric glucose. Disrupting the expression of the neuronal lactate transporter MCT2 also leads to amnesia that is unaffected by either L-lactate or glucose, suggesting that lactate import into neurons is necessary for long-term memory. Glycogenolysis and astrocytic lactate transporters are also critical for the induction of molecular changes required for memory formation, including the induction of phospho-CREB, Arc, and phospho-cofilin. We conclude that astrocyte-neuron lactate transport is required for long-term memory formation.
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► Learning results in glycogenolysis-dependent lactate increase in the hippocampus ► Inhibiting glycogenolysis in the hippocampus blocks long-term memory and LTP ► Knockdown of astrocytic lactate transporters abolishes long-term memory ► Knockdown of neuronal lactate transporter abolishes long-term memory
Summary Background Tuberculosis incidence in the UK has risen in the past decade. Disease control depends on epidemiological data, which can be difficult to obtain. Whole-genome sequencing can detect ...microevolution within Mycobacterium tuberculosis strains. We aimed to estimate the genetic diversity of related M tuberculosis strains in the UK Midlands and to investigate how this measurement might be used to investigate community outbreaks. Methods In a retrospective observational study, we used Illumina technology to sequence M tuberculosis genomes from an archive of frozen cultures. We characterised isolates into four groups: cross-sectional, longitudinal, household, and community. We measured pairwise nucleotide differences within hosts and between hosts in household outbreaks and estimated the rate of change in DNA sequences. We used the findings to interpret network diagrams constructed from 11 community clusters derived from mycobacterial interspersed repetitive-unit–variable-number tandem-repeat data. Findings We sequenced 390 separate isolates from 254 patients, including representatives from all five major lineages of M tuberculosis . The estimated rate of change in DNA sequences was 0·5 single nucleotide polymorphisms (SNPs) per genome per year (95% CI 0·3–0·7) in longitudinal isolates from 30 individuals and 25 families. Divergence is rarely higher than five SNPs in 3 years. 109 (96%) of 114 paired isolates from individuals and households differed by five or fewer SNPs. More than five SNPs separated isolates from none of 69 epidemiologically linked patients, two (15%) of 13 possibly linked patients, and 13 (17%) of 75 epidemiologically unlinked patients (three-way comparison exact p<0·0001). Genetic trees and clinical and epidemiological data suggest that super-spreaders were present in two community clusters. Interpretation Whole-genome sequencing can delineate outbreaks of tuberculosis and allows inference about direction of transmission between cases. The technique could identify super-spreaders and predict the existence of undiagnosed cases, potentially leading to early treatment of infectious patients and their contacts. Funding Medical Research Council, Wellcome Trust, National Institute for Health Research, and the Health Protection Agency.
Neuroacanthocytosis syndromes Jung, Hans H; Danek, Adrian; Walker, Ruth H
Orphanet journal of rare diseases,
10/2011, Volume:
6, Issue:
1
Journal Article
Peer reviewed
Open access
Neuroacanthocytosis (NA) syndromes are a group of genetically defined diseases characterized by the association of red blood cell acanthocytosis and progressive degeneration of the basal ganglia. NA ...syndromes are exceptionally rare with an estimated prevalence of less than 1 to 5 per 1'000'000 inhabitants for each disorder. The core NA syndromes include autosomal recessive chorea-acanthocytosis and X-linked McLeod syndrome which have a Huntington's disease-like phenotype consisting of a choreatic movement disorder, psychiatric manifestations and cognitive decline, and additional multi-system features including myopathy and axonal neuropathy. In addition, cardiomyopathy may occur in McLeod syndrome. Acanthocytes are also found in a proportion of patients with autosomal dominant Huntington's disease-like 2, autosomal recessive pantothenate kinase-associated neurodegeneration and several inherited disorders of lipoprotein metabolism, namely abetalipoproteinemia (Bassen-Kornzweig syndrome) and hypobetalipoproteinemia leading to vitamin E malabsorption. The latter disorders are characterized by a peripheral neuropathy and sensory ataxia due to dorsal column degeneration, but movement disorders and cognitive impairment are not present. NA syndromes are caused by disease-specific genetic mutations. The mechanism by which these mutations cause neurodegeneration is not known. The association of the acanthocytic membrane abnormality with selective degeneration of the basal ganglia, however, suggests a common pathogenetic pathway. Laboratory tests include blood smears to detect acanthocytosis and determination of serum creatine kinase. Cerebral magnetic resonance imaging may demonstrate striatal atrophy. Kell and Kx blood group antigens are reduced or absent in McLeod syndrome. Western blot for chorein demonstrates absence of this protein in red blood cells of chorea-acanthocytosis patients. Specific genetic testing is possible in all NA syndromes. Differential diagnoses include Huntington disease and other causes of progressive hyperkinetic movement disorders. There are no curative therapies for NA syndromes. Regular cardiologic studies and avoidance of transfusion complications are mandatory in McLeod syndrome. The hyperkinetic movement disorder may be treated as in Huntington disease. Other symptoms including psychiatric manifestations should be managed in a symptom-oriented manner. NA syndromes have a relentlessly progressive course usually over two to three decades.
Chorea is a common movement disorder which can be caused by a large variety of diseases including neurodegenerative diseases, metabolic diseases, and autoimmune diseases, or can be secondary to ...structural changes. The basal ganglia seem to be mainly involved in the pathophysiology indicating the vulnerability of this region. The diagnosis can be challenging, especially if chorea occurs during the treatment of neuropsychiatric conditions, and in these cases, it is difficult to distinguish between medication side effects (i.e., tardive dyskinesia) and the development of a neurodegenerative disease. Most therapeutic approaches are predominantly symptomatic, with a focus on multidisciplinary care for many patients. Nevertheless, some underlying diseases can be successfully treated and must not be missed. In this review, we summarize recent new developments in the differential diagnosis of chorea syndromes and suggest a pathway for a successful diagnosis of chorea in infancy, childhood, and adulthood for daily practice.
Chorea is primarily due to an imbalance of basal ganglia output pathways, often due to dysfunction or degeneration of the caudate nucleus and putamen, and can be due to many causes.
We reviewed the ...recent literature to identify newly-recognized causes of chorea, including auto-immune, metabolic, and genetic. We also focused upon developments in mechanisms relating to underlying pathophysiology of certain genetic choreas and advances in therapeutics.
Novel autoantibodies continue to be identified as causes of chorea. Both COVID-19 infection and vaccination are reported to result rarely in chorea, although in some cases causality is not clearly established. Advances in genetic testing continue to find more causes of chorea, and to expand the phenotype of known genetic disorders. Deep brain stimulation can be successful in certain circumstances.
Our understanding of mechanisms underlying this movement disorder continues to advance, however much remains to be elucidated.
•Newly-recognized causes of chorea, including auto-immune, metabolic, and genetic.•Novel autoantibodies continue to be identified as causes of chorea.•Both COVID-19 infection and vaccination are reported to result rarely in chorea.•Advances in genetic testing continue to find more causes of chorea, and to expand the phenotype of known genetic disorders.•Deep brain stimulation can be successful in certain circumstances.
There can be some overlap in the appearance of these two hyperkinetic, irregular movement disorders, and electrophysiological testing is occasionally required to distinguish the two. However, I would ...argue that the rapid, jerky movements seen in the video strongly suggest myoclonus. I could not tell from the report, but it appeared that the movements were increased with volitional movement, which is characteristic of myoclonus, rather than chorea. KCI Citation Count: 1
Anaplastic Lymphoma Kinase (Alk) is a Receptor Tyrosine Kinase (RTK) activated in several cancers, but with largely unknown physiological functions. We report two unexpected roles for the Drosophila ...ortholog dAlk, in body size determination and associative learning. Remarkably, reducing neuronal dAlk activity increased body size and enhanced associative learning, suggesting that its activation is inhibitory in both processes. Consistently, dAlk activation reduced body size and caused learning deficits resembling phenotypes of null mutations in dNf1, the Ras GTPase Activating Protein-encoding conserved ortholog of the Neurofibromatosis type 1 (NF1) disease gene. We show that dAlk and dNf1 co-localize extensively and interact functionally in the nervous system. Importantly, genetic or pharmacological inhibition of dAlk rescued the reduced body size, adult learning deficits, and Extracellular-Regulated-Kinase (ERK) overactivation dNf1 mutant phenotypes. These results identify dAlk as an upstream activator of dNf1-regulated Ras signaling responsible for several dNf1 defects, and they implicate human Alk as a potential therapeutic target in NF1.
ABSTRACT
This study aimed to elucidate the genetic causes underlying early‐onset Parkinsonism (EOP) in a consanguineous Iranian family. To attain this, homozygosity mapping and whole‐exome sequencing ...were performed. As a result, a homozygous mutation (c.773G>A; p.Arg258Gln) lying within the NH2‐terminal Sac1‐like inositol phosphatase domain of polyphosphoinositide phosphatase synaptojanin 1 (SYNJ1), which has been implicated in the regulation of endocytic traffic at synapses, was identified as the disease‐segregating mutation. This mutation impaired the phosphatase activity of SYNJ1 against its Sac1 domain substrates in vitro. We concluded that the SYNJ1 mutation identified here is responsible for the EOP phenotype seen in our patients probably due to deficiencies in its phosphatase activity and consequent impairment of its synaptic functions. Our finding not only opens new avenues of investigation in the synaptic dysfunction mechanisms associated with Parkinsonism, but also suggests phosphoinositide metabolism as a novel therapeutic target for Parkinsonism.
In this study we identified a mutation in synaptojanin 1 as a cause of early‐onset progressive Parkinsonism and generalized seizures. This mutation impaired the phosphatase activity of synaptojanin 1 against its Sac1 domain substrates in vitro, suggesting that defects in phosphoinositide metabolism at synapse may play an important role in the development of Parkinsonism. This finding opens new avenues of investigation in the field of Parkinson research and suggests phosphoinositide metabolism as a novel therapeutic target for Parkinsonism.
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