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PubMed2003

Disruption of Cnp1 uncouples oligodendroglial functions in axonal support and myelination.

Myelination of axons by oligodendrocytes enables rapid impulse propagation in the central nervous system. But long-term interactions between axons and their myelin sheaths are poorly understood. Here we show that Cnp1, which encodes 2',3'-cyclic nucleotide phosphodiesterase in oligodendrocytes, is essential for axonal survival but not for myelin assembly. In the absence of glial cyclic nucleotide phosphodiesterase, mice developed axonal swellings and neurodegeneration throughout the brain, leading to hydrocephalus and premature death. But, in contrast to previously studied myelin mutants, the ultrastructure, periodicity and physical stability of myelin were not altered in these mice. Genetically, the chief function of glia in supporting axonal integrity can thus be completely uncoupled from its function in maintaining compact myelin. Oligodendrocyte dysfunction, such as that in multiple sclerosis lesions, may suffice to cause secondary axonal loss.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗
PubMed2003

Histone H3 is aberrantly phosphorylated in glutamine-repeat diseases.

Double-labeling immunohistochemical studies staining with anti-ubiquitin and anti-phosphoserine antibodies and application of an enzymatic dephosphorylation technique reveal neuronal inclusions and affected nuclei to be aberrantly phosphorylated in brain tissues with patients with glutamine-repeat diseases. Regional distribution of the phosphorylated nuclei in neurons correlates with the pathology. To identify the target nuclear protein, transient expression of Huntington's disease exon 1 gene containing an expanded glutamine repeat was generated in a cell culture and nuclear inclusions were isolated with a fluorescence-activated cell sorting system. Immunoblotting studies of the aggregated nuclear proteins using anti-phosphoserine antibody demonstrate the protein of the aberrant phosphorylation as histone H3. The immunoblots of control and diseased brain tissues demonstrate that the phosphorylation of histone H3 is commonly increased in the diseased brains. Aberrant phosphorylation of histone H3 is surmised to be a shared pathological process in glutamine-repeat diseases.

Adult↗
PubMed2001

Chromosome 13 dementia syndromes as models of neurodegeneration.

Two hereditary conditions, familial British dementia (FBD) and familial Danish dementia (FDD), are associated with amyloid deposition in the central nervous system and neurodegeneration. The two amyloid proteins, ABri and ADan, are degradation products of the same precursor molecule BriPP bearing different genetic defects, namely a Stop-to-Arg mutation in FBD and a ten-nucleotide duplication-insertion immediately before the stop codon in FDD. Both de novo created amyloid peptides have the same length (34 amino acids) and the same post-translational modification (pyroglutamate) at their N-terminus. Neurofibrillary tangles containing the classical paired helical filaments as well as neuritic components in many instances co-localize with the amyloid deposits. In both disorders, the pattern of hyperphosphorylated tau immunoreactivity is almost indistinguishable from that seen in Alzheimer's disease. These issues argue for the primary importance of the amyloid deposits in the mechanism(s) of neuronal cell loss. We propose FBD and FDD, the chromosome 13 dementia syndromes, as models to study the molecular basis of neurofibrillary degeneration, cell death and amyloid formation in the brain.

Amino Acid Sequence↗
PubMed2000

Late-onset neurodegenerative diseases--the role of protein insolubility.

Recently, mutations of the alpha-synuclein gene were found to cause dominantly inherited Lewy-body Parkinson's disease (PD) and alpha-synuclein was identified as a major component of the Lewy body. However, the cause of the common form of PD, with a multifactorial rather than autosomal dominant inheritance pattern, remains unknown. Alpha-synuclein precipitates slowly and apparently spontaneously at high concentration in solution and the mutations that cause PD accelerate precipitation. Other dominantly inherited late-onset or adult-onset dominantly inherited neurodegenerative diseases are associated with precipitation of proteins. In Alzheimer disease, beta-amyloid and tau abnormalities are present and in prion disorders, prion proteins are found. In Huntington disease, a disorder with expanded CAG repeats, huntingtin precipitates occur. In dominantly inherited spinocerebellar ataxias, also expanded CAG repeat disorders, the corresponding ataxin protein precipitates are found. In multiple system atrophy, alpha-synuclein precipitates are encountered and in progressive supranuclear palsy, tau precipitates occur. In familial amyotrophic lateral sclerosis, a group of dominantly inherited disorders, SOD1 precipitates are found. Most of these disorders can involve the basal ganglia in some way. Since similar processes seem to affect neurons of adults or older individuals and since a relatively limited group of proteins seems to be involved, each producing a form of neurodegeneration, it is possible that certain common features are present that affect this group of proteins. Candidates include a conformational shift, as in prions, an abnormality of the ubiquitin-proteosome pathway, as seen in PD, an abnormality of a pathway preventing precipitation (e.g. chaperonins), or potentiation of a pathway promoting precipitation (e.g. gamma-glutamyl-transpeptidase) or apoptosis. Elucidation of the pathways causing this protein insolubilisation is the first step towards approaching prevention and reversal in these late-onset neurodegenerative diseases.

Adult↗
PubMed2003

Neuronal loss in familial frontotemporal dementia with ubiquitin-positive, tau-negative inclusions.

The neuronal density in the frontal, temporal, and parietal lobes was determined in nine cases of familial frontotemporal dementia with ubiquitin-positive, tau-negative inclusions (FTDU). The mean age at onset was 56.9 +/- 2.2 years and the duration of disease was 6.7 +/- 0.5 years. The mean age at death was 63.6 +/- 2.2 years. There was substantial loss (34%) of brain weight (877 +/- 73 g) in the familial cases in comparison with 10 normal aged controls (1326 +/- 50 g, P < 0.001). All of the familial FTDU cases showed atrophy of the frontal, temporal, and parietal lobes; neuronal loss; vacuolation in superficial laminae; reactive astrocytosis; and ubiquitin-positive, tau-negative intracytoplasmic and intranuclear inclusions and dystrophic neurites in varying sites and numbers. Neuronal loss was estimated in nine cases of familial FTDU and in 10 aged controls using a stereological probe, the optical "disector," and a computerized stereology system (CAST-Grid, Olympus, Denmark). There was a significant reduction in neuronal density in the frontal lobe (22.3 +/- 3.8 x 10(3)/mm(3)) of familial FTDU in comparison to aged controls (33.1 +/- 1.7 x 10(3) per mm(3), P < 0.05). An estimate of the relative numbers of neurons was calculated by multiplying the numerical density by the cortical thickness, which showed a striking loss of neurons of 56% in the frontal lobe, 52% loss in the temporal lobe, and a 49% loss in the parietal lobe of familial FTDU when compared to controls. This study shows that familial FTDU has profound focal neuronal loss in multiple association areas that relate to the clinical symptoms characteristic of the disease.

Adult↗
PubMed2003

Progressive neurodegeneration in Drosophila: a model system.

The Drosophila model system has been used to study neurodegenerative diseases by expression of human disease genes in transgenic flies. A different approach is to isolate and characterize Drosophila mutants with progressive neurodegeneration to find novel genes required for brain integrity. Mammalian homologues of these genes might be the genetic basis for some of the various progressive neurodegeneration diseases in humans. Here we describe several such mutants. Some of them reveal degeneration in specific parts of the brain while others affect all brain regions. Cell death can occur through apoptosis or necrosis. In one case, mutant flies show abnormal behavior prior to obvious degeneration while most other mutants reveal such defects only in later stages. These mutants offer a new approach to study basic mechanisms of neurodegeneration and for developing fly models for human diseases.

Animals↗
PubMed2001

Cognitive deficits associated with a recently reported familial neurodegenerative disease: familial encephalopathy with neuroserpin inclusion bodies.

BACKGROUND: We recently discovered an autosomal dominant disease causing a progressive dementia. The disease is caused by a point mutation in the gene coding for the serine protease inhibitor (ie, serpin) neuroserpin. The mutation results in an unstable neuroserpin protein that readily aggregates into intraneuronal inclusions that we identify as Collins bodies. The bodies are distributed throughout the cerebral hemispheres but are significantly more numerous in the cortex and the substantia nigra. We have named the disease familial encephalopathy with neuroserpin inclusion bodies (FENIB). OBJECTIVES: To describe the cognitive and neurophysiological changes exhibited by individuals with FENIB and to correlate the phenotypic expression of the disease with the neuropathological findings. DESIGN: Multiple case studies using neuropsychological assessment, electroencephalography (EEG), magnetic resonance imaging (MRI), and single-photon emission computed tomographic (SPECT) studies of family members were performed. Using these measures, we also compared family members in whom the mutation is present with family members in whom the mutation was absent to control for nonspecific familial factors. SUBJECTS: Nine individuals (5 women, aged 31-64 years; 4 men, aged 43-67 years) from 2 generations of family members related to the first reliably identified individual with symptoms of this disease. Symptoms, by self-report and reports of other family members, ranged from asymptomatic to severe dementia. Six of the 9 individuals carried the disease mutation. RESULTS: All subjects with the mutation demonstrated some cognitive changes, with the greatest demonstrated by subjects older than 40 years. The changes included restricted attention, concentration, and response regulation functions, reduced controlled oral fluency (word-list generation), and restricted visuospatial organization. In general, recall memory was not as affected as other cognitive domains. The most severely affected subject demonstrated global dementia with prominent frontal lobe features. Findings on SPECT showed anomalies limited to frontal areas in the less affected subjects and more global, patchy areas of hypoperfusion in the more severely affected subjects. The 3 oldest and most affected subjects demonstrated slowing on EEG findings. The MRI findings were noncontributory except in the 2 most severe cases, which showed global cortical atrophy. CONCLUSIONS: Cognitive changes in mildly to moderately affected subjects were characterized by deficits in frontal and frontal-subcortical area-dependent processes. Continued progressive deterioration of cerebral functions with relative sparing of recall memory suggests a unique dementia associated with this disease.

Adult↗
PubMed2000

Redefinition: coping with normal results from predictive gene testing for neurodegenerative disorders.

The purpose of this qualitative study was to describe the psychosocial impact and coping processes of normal (negative) results from predictive testing for an inherited neurodegenerative disease. Ten adults with normal results of predictive testing for the Huntington disease (HD) or the Pallido-Ponto-Nigral Degeneration (PPND) gene mutation participated in semi-structured interviews 1 month after receiving results, and seven of these participants were interviewed 6 months later. The major theme of Redefinition was derived using Knafl and Webster's analysis method (1988). People who received normal gene results experienced loss of former beliefs about themselves and developed new self definitions, relationships with family, and roles in society. This coping process evolved from a personal focus at 1 month to a broader future perspective at 6 months after testing. Identifying components of the redefinition process may be an important consideration in planning interventions to promote coping with normal gene results in persons within at-risk families.

Adaptation, Psychological↗
PubMed2003

Leukodystrophy associated with oligodontia in a large inbred family: fortuitous association or new entity?

We describe a large inbred Syrian pedigree with an autosomal recessive neurodegenerative disorder. The clinical picture of the affected patients is oligodontia, and a degenerative neurological condition with onset around age 12, characterized by progressive ataxia and pyramidal syndrome. Abnormalities in the white matter and cortical atrophy were assessed by magnetic resonance imaging. Differential diagnosis and the possibility of a fortuitous association or the report of a hitherto unreported dento-leukoencephalopathy are discussed.

Adolescent↗
PubMed2001

A disorder similar to Huntington's disease is associated with a novel CAG repeat expansion.

Huntington's disease (HD) is an autosomal dominant disorder characterized by abnormalities of movement, cognition, and emotion and selective atrophy of the striatum and cerebral cortex. While the etiology of HD is known to be a CAG trinucleotide repeat expansion, the pathways by which this mutation causes HD pathology remain unclear. We now report a large pedigree with an autosomal dominant disorder that is clinically similar to HD and that arises from a different CAG expansion mutation. The disorder is characterized by onset in the fourth decade, involuntary movements and abnormalities of voluntary movement, psychiatric symptoms, weight loss, dementia, and a relentless course with death about 20 years after disease onset. Brain magnetic resonance imaging scans and an autopsy revealed marked striatal atrophy and moderate cortical atrophy, with striatal neurodegeneration in a dorsal to ventral gradient and occasional intranuclear inclusions. All tested affected individuals, and no tested unaffecteds, have a CAG trinucleotide repeat expansion of 50 to 60 triplets, as determined by the repeat expansion detection assay. Tests for the HD expansion, for all other known CAG expansion mutations, and for linkage to chromosomes 20p and 4p were negative, indicating that this mutation is novel. Cloning the causative CAG expansion mutation for this new disease, which we have termed Huntington's disease-like 2, may yield valuable insight into the pathogenesis of HD and related disorders.

Adult↗
PubMed2003

Hprt(CAG)146 mice: age of onset of behavioral abnormalities, time course of neuronal intranuclear inclusion accumulation, neurotransmitter marker alterations, mitochondrial function markers, and susceptibility to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

We reported previously a model of polyglutamine repeat disorders with insertion of 146 CAG repeats into the murine hypoxanthine phosphoribosyl transferase locus (Hprt(CAG)146; Ordway et al. [1997] Cell 91:753-763), which does not normally contain polyglutamine repeats. These mice develop an adult-onset neurologic phenotype of incoordination, involuntary limb clasping, seizures, and premature death. Histologic analysis demonstrates widespread ubiquinated neuronal intranuclear inclusions (NIIs). We now report characterization of the age of onset of behavioral abnormalities, correlated with the time course of occurrence of NIIs in several brain regions, and the occurrence of NIIs in non-neuronal tissues. Onset of behavioral abnormalities occurred at approximately 22 weeks of age. There was variable time course of expression of NIIs in several brain regions. Assessment of several non-neuronal tissues revealed nuclear inclusions in hepatocytes and choroid plexus epithelium. Gamma-aminobutyric acid (GABA)/benzodiazepine receptors, dopamine D1-like and D2-like receptors, and type 2 vesicular monoamine transporter (VMAT2) binding sites were assayed before and after the onset of behavioral abnormalities. GABA/benzodiazepine receptors were unchanged either before or after the onset of behavioral abnormalities in any region analyzed, whereas striatal D1-like and D2-like receptors were diminished after but not before the onset of symptoms. Dorsal striatal VMAT2 binding sites were decreased before the onset of behavioral changes. Mitochondrial electron transport chain components were assayed with histochemical methods before and after the onset of behavioral changes. There was no change in behaviorally presymptomatic or symptomatic animals. Hprt(CAG)146 mice did not exhibit increased susceptibility to the mitochondrial toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Hprt(CAG)146 mice are a useful model for studying polyglutamine repeat disorders.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2000

A clone contig of 12q24.3 encompassing the distal hereditary motor neuropathy type II gene.

We previously assigned the disease locus for autosomal dominant hereditary motor neuropathy type II (distal HMN II) within a 13-cM interval at chromosome 12q24.3. We constructed a physical map of the distal HMN II region based on yeast artificial chromosomes (YACs), P1 artificial chromosomes (PACs), and bacterial artificial chromosomes (BACs) using an STS content mapping approach. The contig contains 26 YAC, 15 PAC, and 60 BAC clones and covers a physical distance of approximately 5 Mb. A total of 99 STS markers, including 25 known STSs and STRs, 49 new STSs generated from clone end-fragments, 20 ESTs, and 5 known genes, were located on the contig. This physical map provides a valuable resource for mapping genes and markers located within the distal HMN II region and facilitates the positional cloning of the distal HMN II gene.

Bacteriophage P1↗
PubMed2000

Infantile-onset leukoencephalopathy with discrepant mild clinical course.

Four children characterised by megalencephaly and cerebral leukoencephalopathy with infantile onset, defined on the basis of clinical and neuroimaging findings are reported. The course of the disease is characterised by stabilization of the macrocephaly and slow clinical deterioration. The CT scan findings include supratentorial diffuse hypodensities in the white matter and swelling. The characteristic MRI findings include the discrepant severity in comparison with the clinical picture, diffuse supratentorial white matter abnormalities with subcortical cysts. The basic defect of the disease is unknown. Considering the high rate of consanguinity among the parents and the presence of two affected sibs in one family, an autosomal recessive inheritance is assumed. We report four unrelated cases of this entity.

Brain↗
PubMed2003

Neuromelanin and its interaction with iron as a potential risk factor for dopaminergic neurodegeneration underlying Parkinson's disease.

Neuromelanin (NM) is a granular, dark brown pigment produced in some but not all of the dopaminergic neurons of the human substantia nigra (SN). In Parkinson's disease (PD) the pigmented dopaminergic neurons of the SN degenerate, suggesting that this process is related to the presence of NM. As yet it is unknown whether NM in the parkinsonian brain differs from that found in healthy tissue and thus may fulfil a different role within this tissue. The function of NM within the pigmented neurons is unknown but other melanins are believed to play a protective role via attenuation of free radical damage. Experimental evidence suggests that NM may also exhibit this characteristic, possibly by direct inactivation of free radical species or via its ability to chelate transition metals, such as iron. NM has the ability to bind a variety of metals, seven per cent of isolated NM is reported to consist of Fe, Cu, Zn and Cr. Iron is of particular interest as this metal is highly concentrated within the SN. Up to 20 per cent of the total iron contained in the SN from normal subjects is bound within NM. Further, it was demonstrated that NM contains a protein component and that iron is bound to NM in the ferric form. Increased tissue iron found in the parkinsonian SN may saturate iron-chelating sites on NM, and a looser association between iron and NM may result in an increased, rather than decreased, production of free radical species. It is hypothesized that this redox-active iron could be released and involved in a Fenton-like reaction leading to an increased production of oxidative radicals. The resultant radical-mediated cytotoxicity may contribute to cellular damage observed in PD.

Dopamine↗