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Regulation of cytoskeletal dynamics is essential to neuronal plasticity during development and adulthood. Dysregulation of these mechanisms may contribute to neuropsychiatric and neurodegenerative diseases. The neuronal protein kinase, cyclin-dependent kinase 5 (Cdk5), is involved in multiple aspects of neuronal function, including regulation of cytoskeleton. A neuroproteomic search identified the tubulin-binding protein, stathmin, as a novel Cdk5 substrate. Stathmin was phosphorylated by Cdk5 in vitro at Ser25 and Ser38, previously identified as mitogen-activated protein kinase (MAPK) and p38 MAPKδ sites. Cdk5 predominantly phosphorylated Ser38, while MAPK and p38 MAPKδ predominantly phosphorylated Ser25. Stathmin was phosphorylated at both sites in mouse brain, with higher levels in cortex and striatum. Cdk5 knockout mice exhibited decreased phospho-Ser38 levels. During development, phospho-Ser25 and -Ser38 levels peaked at post-natal day 7, followed by reduction in total stathmin. Inhibition of protein phosphatases in striatal slices caused an increase in phospho-Ser25 and a decrease in total stathmin. Interestingly, the prefrontal cortex of schizophrenic patients had increased phospho-Ser25 levels. In contrast, total and phospho-Ser25 stoichiometries were decreased in the hippocampus of Alzheimer's patients. Thus, microtubule regulatory mechanisms involving the phosphorylation of stathmin may contribute to developmental synaptic pruning and structural plasticity, and may be involved in neuropsychiatric and neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

Reports on the investigation of a delayed death following injury in an automobile accident. Occurrence of the hemorrhage after the accident; Hospitalization of the patient for skeletal trauma; Absence of symptoms of brain injury; Findings of the autopsy.

Huntington disease (HD) is caused by the expansion of a CAG repeat within the HD gene yielding an abnormal huntingtin protein (Htt) with an expanded polyglutamine repeat near the N-terminus. A fragment of the protein containing this repeat accumulates in neurons, forming aggregates. While the presence of these aggregates' is a marker for HD, the effect of Htt aggregates is still unknown. To identify locations in the CNS of HD patients that contain these aggregates, we employed a monoclonal antibody to a 38 polyglutamine repeat (Chemicon) to stain paraffin sections of various regions of formalin-fixed, postmortem CNS tissue from 12 HD patients. Sections were treated with formic acid prior to immunostaining. Abnormal polyglutamine immunoreactivity was identified in cortical neurons of all 4 cerebral lobes, entorhinal cortex, subiculum, lateral geniculate body, locus coeruleus, dentate and pontine nuclei, and spinal cord grey matter. In the medulla, multiple cranial nerve nuclei and scattered neurons of the reticular formation demonstrated staining. Areas that failed to stain included the pituitary and pineal glands, white matter, and. cerebellar cortex. These data indicate that abnormal Htt can be found in diverse CNS locations in a distribution pattern that is non-random and reproducible and suggest that HD may affect populations of neurons that were not previously known to be involved in that disorder. [ABSTRACT FROM AUTHOR]

Alzheimer disease-type tau pathology is common in the brains of patients with Down syndrome (DS) and occurs at an earlier age than in the general population. These tau-containing lesions have not been fully characterized. We set out to determine if a characteristic pattern for 3-repeat (3R) and 4-repeat (4R) tau isoforms of phosphorylated tau protein exists in neurofibrillary tangles (NFT) of the Alzheimer type seen in DS. Sections of hippocampus and entorhinal cortex from autopsy brains of 19 DS patients -- 8 under age 40 and 11 over age 40 (age range 3 months to 66 years) -- were stained with monoclonal antibodies to 3R tau (RD3) and 4R tau (RD4). NFT were present in all patients over age 40. Intracellular NFT stained with 3R and 4R antibodies. Extracellular (ghost) NFT showed preferential 3R immunoreactivity with uniform staining of lesser intensity than intracellular NFT. The preferential 3R staining of ghost NFT in DS brains is similar to that recently reported in Alzheimer disease and tangle predominant senile dementia. [ABSTRACT FROM AUTHOR]

Recently, TDP-43 was identified as a component of the inclusions in frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U). Aims: (1) To examine the extent of TDP-43 pathology in FTLD-U cases, including cases with sparse or regionally limited ubiquitinated inclusions; (2) To confirm the absence of TDP-43 pathology in other diseases. Methods: Forty brain autopsy cases of FTLD-U were obtained from the Midwest-Southwest Consortium for FTLD. Twenty cases of other neurodegenerative diseases and 5 controls were also studied. Methods: IHC was performed with polyclonal antibodies to TDP-43 (ProteinTech; 1:1,000) and ubiquitin (Dako; 1:500). Two IHC methods were used: routine and enhanced. The enhanced method included the use of the Benchmark XT automated stainer and ultra View Red detection system (Ventana). Results: A particularly striking pattern of pathology was seen in 6 of 18 cases where the hippocampus was stained with the enhanced method and consisted of frequent dystrophic neurites in the CA1 region. Four of five cases also showed frequent dystrophic neurites in the frontal cortex. No TDP-43-pathology was identified in other diseases or controls. Conclusion: Extensive TDP-43-immunoreactive neuritic pathology may characterize most cases of FTLD-U. [ABSTRACT FROM AUTHOR]