geranylgeranylacetone and Neurodegenerative-Diseases

In response to stresses, mammalian cells induce heat shock proteins (HSP). Overproduction of a stress-inducible 70-kDa protein (Hsp70) results in the acquisition of tolerance against various types of stresses. An acyclic isoprenoid, geranylgeranylacetone (GGA), was introduced for the first time as a non-toxic Hsp 70 inducer, which selectively and safely induced Hsp70 in cultured guinea pig gastric mucosal cells and rat gastric mucosa. GGA also primed other types of cells for enhanced induction of Hsp70, when exposed to stress. Pretreatment of rats with GGA markedly suppressed ischemia-reperfusion injury of the liver, small intestine, or heart, and improved survival after 95% hepatectomy as well as liver transplantation. GGA can block insult-induced apoptosis at multiple levels; it inhibited activation of c-Jun N-terminal kinases, decline of mitochondrial membrane potential, and formation of apoptosome by binding with Apaf-1. Recently, GGA has been shown to induce thioredoxin and anti-viral genes, suggesting that GGA may exhibit protective actions independently of Hsp70 induction. HSP are members of molecular chaperones that are essential for the quality control of intracellular proteins. New compounds specifically targeting molecular chaperones that function to prevent the accumulation of misfolded proteins may be useful for the treatment of neurodegenerative disorders in the near future.

Topics: Animals; Apoptosis; Cytoprotection; Digestive System Diseases; Diterpenes; Gastric Mucosa; Guinea Pigs; HSP70 Heat-Shock Proteins; Humans; JNK Mitogen-Activated Protein Kinases; Membrane Potentials; Mitochondria; Mitogen-Activated Protein Kinases; Neurodegenerative Diseases; Rats; Reperfusion Injury

Neurodegenerative diseases including amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, and polyglutamine (polyQ) diseases are thought to be caused by protein misfolding. Heat shock proteins (HSPs), which function mainly as molecular chaperones, play an important role in the folding and quality control of proteins. The histopathological hallmark of neurodegenerative diseases is accumulation and/or inclusions of the disease-causing proteins in residual neurons in targeted regions of the nervous system. The inclusions combine with many components of molecular chaperone pathways and ubiquitin-proteasome, raising the possibility that misfolding and altered degradation of mutant proteins may be involved in the pathogenesis of neurodegenerative diseases. Overexpression of HSPs has been reported to reduce the number and size of inclusions and accumulation of disease-causing proteins, and ameliorate the phenotypes in neuronal cell and mouse models. Hsp90 inhibitors also exert therapeutic effects through selective proteasome degradation of its client proteins. Elucidation of its pathophysiology using animal models has led to the development of disease-modifying drugs, i.e., Hsp90 inhibitor and HSP inducer, which inhibit the pathogenic process of neuronal degeneration. These findings may provide the basis for development of an HSP-related therapy for neurodegenerative diseases.

Topics: Animals; Diterpenes; Heat-Shock Proteins; HSP90 Heat-Shock Proteins; Mice; Neurodegenerative Diseases; Proteasome Endopeptidase Complex; Protein Folding; Ubiquitin