Biomedical subjects

Bitao Bu

Publications and source records attributed to Bitao Bu.

4 recordsLinked to original sources

PubMed2004

Cyclin-dependent kinase inhibitors attenuate protein hyperphosphorylation, cytoskeletal lesion formation, and motor defects in Niemann-Pick Type C mice.

Dysregulation of cyclin-dependent kinases (cdks) and cytoskeletal protein hyperphosphorylation characterizes a subset of human neurodegenerative diseases, including Alzheimer's disease, amyotrophic lateral sclerosis, and Niemann-Pick Type C (NPC). It is thought that these cytoskeletal changes lead eventually to development of hallmark cytoskeletal lesions such as neurofibrillary tangles and axonal spheroids. Although many studies support an involvement of cdks in these neurodegenerative cascades, it is not known whether cdk activity is essential. The naturally occurring npc-1 mutant mouse mimics human NPC, in displaying activation of cdk5, mitotic cdc2, and cdk4, with concomitant cytoskeletal pathology and neurodegeneration. We availed of this model and specific pharmacological inhibitors of cdk activity, to determine whether cdks are necessary for NPC neuropathology. The inhibitors were infused intracerebroventricularly for a 2-week period, initiated at a pathologically incipient stage. While an inactive stereoisomer, iso-olomoucine, was ineffective, two potent inhibitors, roscovitine and olomoucine, attenuated significantly the hyperphosphorylation of neurofilament, tau, and mitotic proteins, reduced the number of spheroids, modulated Purkinje neuron death, and ameliorated motor defects in npc mice. These results suggest that cdk activity is required for neuropathology and subsequent motor impairment in NPC. Studies aimed at knocking down individual cdks in these mice will help identify the specific cdk(s) that are essential, and delineate their precise roles in the neurodegenerative process.

Animals↗

PubMed2003

Understanding Niemann-Pick type C disease: a fat problem.

PURPOSE OF REVIEW: Progressive neurological deterioration is the ultimate cause of premature death in Niemann-Pick type C disease. Yet it remains unknown why a defect in basic cellular lipid homeostasis would lead to such profound neurological dysfunction and degeneration. The established belief that the central nervous system disorder of Niemann-Pick type C disease is secondary to lipid accumulation has led to a deficiency of research and information on the neurological manifestation of the disease. Lipid and vesicular trafficking have been studied extensively in non-neuronal cells such as fibroblasts and significant advances have been summarized in excellent reviews. The purpose of the present review is to consolidate the findings on brain lipid metabolism and Niemann-Pick type C disease neuropathology, so as to generate a current picture of the central nervous system disease, and emphasize potential aspects for future research. RECENT FINDINGS: Some key findings in the last couple of years have brought the neurological features of Niemann-Pick type C disease into focus. Most importantly, multiple strategies for reducing lipid overload have proven ineffective in preventing the onslaught of neurodegeneration, while efficiently reducing lipid disturbances in extracerebral tissues. Of much significance was the finding that the central nervous system disease is brain autonomous. Finally, investigation of lipid defects and neuropathological changes in Niemann-Pick type C disease gene-1-deficient mice has shed light on some novel putative therapeutic targets. SUMMARY: The independence of brain pathology from visceral complications in Niemann-Pick type C disease has implications for its treatment. Further studies of the neurological mechanisms underlying the disease will have a significant impact on future clinical diagnosis and management of patients.

Animals↗

PubMed2002

Deregulation of cdk5, hyperphosphorylation, and cytoskeletal pathology in the Niemann-Pick type C murine model.

NPC-1 gene mutations cause Niemann-Pick type C (NPC), a neurodegenerative storage disease resulting in premature death in humans. Spontaneous mutation of the NPC-1 gene in mice generates a similar phenotype, usually with death ensuing by 12 weeks of age. Both human and murine NPC are characterized neuropathologically by ballooned neurons distended with lipid storage, axonal spheroid formation, demyelination, and widespread neuronal loss. To elucidate the biochemical mechanism underlying this neuropathology, we have investigated the phosphorylation of neuronal cytoskeletal proteins in the brains of npc-1 mice. A spectrum of antibodies against phosphorylated epitopes in neurofilaments (NFs) and MAP2 and tau were used in immunohistochemical and immunoblotting analyses of 4- to 12-week-old mice. Multiple sites in NFs, MAP2, and tau were hyperphosphorylated as early as 4 weeks of age and correlated with a significant increase in activity of the cyclin-dependent kinase 5 (cdk5) and accumulation of its more potent activator, p25, a proteolytic fragment of p35. At 5 weeks of age, the development of axonal spheroids was noted in the pons. p25 and cdk5 coaccumulated with hyperphosphorylated cytoskeletal proteins in axon spheroids. These various abnormalities escalated with each additional week of age, spreading to other regions of the brainstem, basal ganglia, cerebellum, and eventually, the cortex. Our data suggest that focal deregulation of cdk5/p25 in axons leads to cytoskeletal abnormalities and eventual neurodegeneration in NPC. The npc-1 mouse is a valuable in vivo model for determining how and when cdk5 becomes deregulated and whether cdk5 inhibitors would be useful in blocking NPC neurodegeneration.

Animals↗

PubMed2002

Niemann-Pick disease type C yields possible clue for why cerebellar neurons do not form neurofibrillary tangles.

It is unknown why cerebellar neurons resist neurofibrillary tangle (NFT) formation. In Niemann-Pick disease Type C (NPC), NFT-mediated neurodegeneration occurs throughout brain, but the cerebellum degenerates conspicuously without NFT. To understand why, we have studied markers of NFT pathogenesis in cerebellum from 17 NPC cases, all having abundant NFT in forebrain. Remarkably, we found that NPC cerebella display several early markers of NFT formation, i.e., hyperphosphorylated tau and an array of cell cycle regulators, suggesting that cerebellar neurons in NPC undergo similar modifications as other neurons that develop NFT. However, cerebellar neurons are deficient in tau, the building block of NFT, and this may be one reason for their inability to form NFT. Even without NFT, cerebellar neurodegeneration may be triggered by the inappropriate activation of the cell cycle cdc2 kinase, and the npc-1 murine model provides an opportunity to test this hypothesis.

Adolescent↗