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ABSTRACT: Lafora disease is a progressive myoclonus epilepsy caused by mutations in the EPM2A gene encoding laforin or in the EPM2B gene encoding malin. It is characterized by the presence of polyglucosan intracellular inclusion bodies (Lafora bodies) in brain and other tissues. Targeted disruption of Epm2a or Epm2b genes in mice produced widespread neuronal degeneration and accumulation of Lafora bodies in neuronal and nonneuronal tissues. Here we analyzed the neurologic alterations produced by disruption of the laforin gene in Epm2a mice and compared them to those in malin-deficient mice. Both Epm2a and Epm2b mice showed altered motor activity, impaired motor coordination, abnormal hind limb clasping, and episodic memory deficits. Epm2a mice also had tonic-clonic seizures, whereas both Epm2a and Epm2b mice had spontaneous single spikes, spike-wave, polyspikes, and polyspike-wave complexes with correlated myoclonic jerks. Neurologic alterations observed in the mutants were comparable and correlated with the accumulation of abundant Lafora bodies in the cerebral cortex, the hippocampus, the basal ganglia, the cerebellum, and the brainstem, suggesting that these inclusions could cause cognitive and behavioral deterioration. Thus, both Epm2a and Epm2b mice exhibit many pathologic aspects seen in patients with Lafora disease and may be valuable for the study of this disorder.
Journal of Neuropathology and Experimental Neurology 04/2012; 71(5):413-21. · 4.26 Impact Factor
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ABSTRACT: Progressive supranuclear palsy (PSP) is a clinicopathological syndrome related to tau deposits and in linkage disequilibrium with tau polymorphisms. Some rare familial PSP cases have been related to tau gene mutations.
To present the clinical, pathological, and molecular data of one family with early-onset autosomal dominant PSP.
We performed clinical examinations, quantitative neurological tests, positron emission tomographic scans with fluorodopa F 18 and raclopride C 11, analysis of tau mutations, neuropathological examinations, and protein analyses on brain specimens.
Three family members had PSP confirmed by pathological features in the proband. A novel mutation of tau, G303V, was found in the proband and other family members. tau Isoforms with 4 microtubule-binding repeats were overexpressed in the proband brain.
The G303V mutation of tau is associated with autosomal dominant PSP. Expression of 4 microtubule-binding repeat tau isoforms is increased in the proband.
Archives of Neurology 10/2005; 62(9):1444-50. · 7.58 Impact Factor
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ABSTRACT: Autosomal recessive-juvenile parkinsonism (AR-JP) is one of the most common forms of familial Parkinson's disease (PD) and is related to mutations in the Park-2 gene, encoding for a protein ligase of ubiquitin, parkin. Different mutations located along the parkin gene have been observed in different AR-JP affected families, possibly interfering with the normal function of parkin and the proteasome system. Two cases of patients with AR-JP have been recently described presenting different homo- and heterozygous parkin mutations and limited tau pathology. We report here the case of a patient with clinical and pathological findings compatible with progressive supranuclear palsy (PSP), carrier of a single, heterozygous mutation of the parkin gene, and homozygous for the H1/H1 haplotype in the tau gene. Abnormal tau hyperphosphorylation has been observed in our patient brain samples, suggesting that a partial deficit of parkin, a protein with ubiquitin-ligase function, may trigger tau pathology in individuals with molecular genetic risk factors.
Journal of Alzheimer's disease: JAD 11/2002; 4(5):399-404. · 3.74 Impact Factor
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ABSTRACT: The maturation of the calcium binding proteins calbindin-D28k (CB) and parvalbumin (PV) during the first 3 postnatal weeks was studied in the rat thalamus using immunohistochemistry. These two proteins display a non-homogeneous distribution in the adult thalamus. In the rat, CB is mainly localized in the neurons and neuropil of the thalamic midline, intralaminar, and ventromedial nuclei, as well as in the posterior complex. At birth, CB-immunoreactive cell bodies were evident in thalamic midline structures, and especially in the nucleus reuniens. The number of thalamic CB-positive cell bodies, as well as the intensity of the neuropil immunostaining, increased progressively in the first postnatal weeks. This quantitative increase was first apparent in the midline structures and then in the other thalamic territories which are CB-positive in adulthood, and followed a mediolateral gradient. The mature pattern was achieved by the end of the third postnatal week. In the adult rat thalamus the neurons of the reticular nucleus display PV-immunostaining and PV-positive fibers densely innervate most of the dorsal thalamic domains. PV-immunoreactivity was clearly evident at birth in the cell bodies of the reticular nucleus. The density of PV-containing fibers increased progressively after birth in the dorsal thalamus, with a lateromedial gradient. At the end of the third postnatal week the ventroposterior (VP) complex appeared heavily innervated by PV-positive fibers, whose density in more medial structures was still lower than in the adult thalamus. A transient hyperinnervation of PV-immunoreactive fibers, displaying a dishomogeneous organization in distinct segments, was observed in VP, and especially in the ventroposteromedial nucleus, during the second postnatal week. Altogether these findings indicate that the maturation of CB and PV requires postnatally a relatively prolonged period of time. The possible involvement of these proteins in different functional aspects of thalamic neuronal maturation is discussed.
Developmental Brain Research 03/1991; · 1.78 Impact Factor
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ABSTRACT: The distribution of the GABAA receptor/benzodiazepine receptor/chloride channel complex was investigated in the thalamus of the rat by means of immunohistochemistry in adulthood, as well as during embryonic and postnatal development, using a monoclonal antibody. In adults, the immunoreactivity for the GABAA receptor complex was intensely expressed by neuronal processes throughout the dorsal thalamus. Neuronal perikaryal membranes were frequently outlined by punctate immunostaining; cell bodies, intrathalamic fibre bundles and the internal capsule did not display immunoreactivity for the GABAA receptor. Regional differences in the expression of the receptor were consistently observed: the immunostaining was much lighter in the thalamic reticular nucleus than in the dorsal thalamic nuclei and, among the latter, the anteroventral nucleus and the ventral nuclear complex displayed the most intense immunopositivity. Immunostaining for the GABAA receptor was already expressed in embryos at E14, and was homogeneously distributed throughout the neuropil of the dorsal and ventral thalamic primordia. During the first two postnatal weeks, a regional differentiation of the immunopositivity was appreciable in the thalamus, with a progressive reduction in the reticular nucleus and a parallel increase in the dorsal thalamic structures. Immunoreactive neuronal perikarya were not observed in the thalamus at any developmental stage. The expression of the GABAA receptor complex appeared to have reached a mature configuration by the end of the third postnatal week. These findings indicate that in adults the GABAA receptor is differentially expressed by thalamic nuclear structures, including the reticular nucleus. Furthermore, the maturation of the receptor in the thalamus undergoes a rearrangement during the first postnatal weeks that results in a considerable regression within the reticular nucleus.
European Journal of Neuroscience 02/1991; 3(2):118-125. · 3.63 Impact Factor
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ABSTRACT: A monoclonal antibody against benzodiazepines (21-7F9) was used to study the distribution of benzodiazepine-like immunoreactivity in the rat brain. Immunodensitometry in combination with image analysis were used for quantification. The results showed a ubiquitous distribution of benzodiazepine-like immunoreactivity throughout the brain. Very high levels of benzodiazepine-like immunoreactivity were found in the Purkinje cell layer of the cerebellum, in the primary olfactory cortex, in the stratum pyramidale of the hippocampus and in the mitral cell layer of the olfactory bulb. High densities of benzodiazepine-like immunoreactivity were found in the granule cell layer of the cerebellum, the pyramidal cell layer of the olfactory tubercle, the granule layer of the dentate gyrus, the arcuate nucleus of the hypothalamus, the mammillary bodies, the interstitial nucleus of Cajal and superficial grey layer of superior colliculus. The substantia nigra pars compacta, the islands of Calleja and layers II, III, V and VI of the cerebral cortex had moderate levels of benzodiazepine-like immunoreactivity. Lower densities were found in the internal granular layer and the external plexiform layer of the olfactory bulb, in the molecular layer of the dentate gyrus, in layers I and IV of the cerebral cortex, in the nucleus caudate-putamen and most of the thalamic nuclei. The lowest density of immunoreactivity was found in the globus pallidus, and the strata radiatum, oriens and lacunosum-moleculare of the hippocampus. The distribution of endogenous benzodiazepine-like immunoreactivity was compared with the distribution of the GABA/benzodiazepine receptor by using both immunocytochemistry and receptor autoradiography. Our studies have shown a clear mismatch between the localization of the benzodiazepine-like immunoreactivity and the GABA/benzodiazepine receptors.
Journal of Chemical Neuroanatomy.
