Autophagic Cell Death (autophagic + cell_death)

Distribution by Scientific Domains

Selected Abstracts

Enhanced autophagic cell death in expanded polyhistidine variants of HOXA1 reduces PBX1-coupled transcriptional activity and inhibits neuronal differentiation

Rubigilda C. Paraguison
Abstract HOXA1 is a member of the homeobox gene family and is involved in early brain development. In our previous study, we identified novel variants of polyhistidine repeat tract in HOXA1 gene and showed that ectopic expression of expanded variants led to enhanced intranuclear aggregation and accelerated cell death in a time-dependent manner. Here, we further investigate the implications of polyhistidine variants on HOXA1 function. Aside from intranuclear aggregation, we observed cytosolic aggregates during the early stages of expression. Rapamycin, an autophagy inducer, resulted in decreased protein aggregation and cell death. Here, we also show an interaction between variants of HOXA1 and one of the HOX protein known cofactors, PBX1. Expanded HOXA1 variants exhibited reduced PBX1-coupled transcriptional activity through a regulatory enhancer of HOXB1. Moreover, we demonstrate that both deleted and expanded variants inhibited neurite outgrowth in retinoic acid-induced neuronal differentiation in neuroblastoma cells. These results provide further evidence that expanded polyhistidine repeats in HOXA1 enhance aggregation and cell death, resulting in impaired neuronal differentiation and cooperative binding with PBX1. 2006 Wiley-Liss, Inc. [source]

Involvement of apoptosis and cholinergic dysfunction in Alzheimer's disease

Abstract As Alzheimer's disease (AD) progresses, brain atrophy becomes conspicuous, and histologically there is neuronal loss, primarily with a deficit of cholinergic neurons observed. Hitherto, the view has been that cell death, apoptosis, plays a role in this neuronal loss. Apoptosis is characterized by the morphological changes of nuclear fragmentation, chromatin condensation and cell shrinkage, with activation of caspases, members of the cysteine protease family, resulting in considerable substrate cleavage. TUNEL positive neurons have in fact been detected in AD brain, indicating increased caspase activity and resulting substrate cleavage. In AD brain, amyloid beta peptides (A,), the main constituent of senile plaque, are a specific pathological hallmark observed in extracellular spaces. In contrast, the main constituent of intracellularly observed neurofibrillary tangles (NFT) is hyperphosphorylated tau, which is observed in various neurodegenerative disorders other than AD. The viewpoint of many studies is that the A, and NFT that cause these neuropathological changes probably participate in neuronal death. However, up until now it has been thought that there was no hypothesis offering a comprehensive explanation of how the accumulation of extracellular A, and intracellular NFT leads to neuronal death. This report first covers the mechanism of apoptosis as clarified by molecular biological methods, and provides an explanation of how apoptosis could be involved in AD pathology. The subject of autophagic cell death, a type of cell death morphology that has recently been the focus of attention, is also addressed. [source]

Tryptamine induces cell death with ultrastructural features of autophagy in neurons and glia: Possible relevance for neurodegenerative disorders

Federico Herrera
Abstract Tryptamine derivatives are a family of biogenic amines that have been suggested to be modulators of brain function at physiological concentrations. However, pharmacological concentrations of these amines display amphetamine-like properties, and they seem to play a role in brain disorders. Amphetamines induce autophagy in nerve cells, and this type of cell death has also been involved in neurodegenerative diseases. In the present work, we clearly demonstrate for the very first time that high concentrations of tryptamine (0.1,1 mM) induce autophagy in HT22 and SK-N-SH nerve cell lines and in primary cultures of astrocytes, glial cells being less sensitive than neurons. Ultrastructural cell morphology shows all of the typical hallmarks of autophagy. There is no nuclear chromatin condensation, endoplasmic reticulum and mitochondria are swollen, and a great number of double-membraned autophagosomes and residual bodies can be shown in the cytoplasm. Autophagosomes and residual bodies contain mitochondria, membranes, and vesicles and remain unabridged until the cell membrane is disrupted and the cell dies. The same results have been found when cells were incubated with high concentrations of 5-methoxytryptamine (0.1,1 mM). Our results establish a possible link between the role of tryptamine derivatives in brain disorders and the presence of autophagic cell death in these kinds of disorders. Anat Rec Part A, 288A:1026,1030, 2006. 2006 Wiley-Liss, Inc. [source]

Deregulation of cell-death pathways as the cornerstone of skin diseases

N. Zutterman
Summary Deregulation of cell-death pathways plays a key role in the pathogenesis of various skin diseases. The different types of cell death are mainly defined by morphological criteria, and include apoptosis, autophagic cell death, and necrosis. The process of apoptosis is well characterized at the molecular level and involves the activation of two main pathways, the intrinsic and extrinsic pathways, converging into the execution of apoptosis by intracellular cysteine proteases, called caspases. The relevance and implication of these apoptotic pathways in the pathophysiology of skin diseases, such as toxic epidermal necrolysis, graft-versus-host disease and skin cancer, has been extensively studied. The role of autophagic cell death in progression of skin tumours and response to cytotoxic drugs is only beginning to be elucidated. [source]