The ubiquitin-proteasome system in spongiform degenerative disorders

Abstract

Spongiform degeneration is characterized by vacuolation in nervous tissue accompanied by neuronal death and gliosis. Although spongiform degeneration is a hallmark of prion diseases, this pathology is also present in the brains of patients suffering from Alzheimer's disease, diffuse Lewy body disease, human immunodeficiency virus (HIV) infection, and Canavan's spongiform leukodystrophy. The shared outcome of spongiform degeneration in these diverse diseases suggests that common cellular mechanisms must underlie the processes of spongiform change and neurodegeneration in the central nervous system. Immunohistochemical analysis of brain tissues reveals increased ubiquitin immunoreactivity in and around areas of spongiform change, suggesting the involvement of ubiquitin-proteasome system dysfunction in the pathogenesis of spongiform neurodegeneration. The link between aberrant ubiquitination and spongiform neurodegeneration has been strengthened by the discovery that a null mutation in the E3 ubiquitin-protein ligase mahogunin ring finger-1 (Mgrn1) causes an autosomal recessively inherited form of spongiform neurodegeneration in animals. Recent studies have begun to suggest that abnormal ubiquitination may alter intracellular signaling and cell functions via proteasome-dependent and proteasome-independent mechanisms, leading to spongiform degeneration and neuronal cell death. Further elucidation of the pathogenic pathways involved in spongiform neurodegeneration should facilitate the development of novel rational therapies for treating prion diseases, HIV infection, and other spongiform degenerative disorders.

Fig. 1

Spongiform degeneration in humans and animals is characterized by vacuolar change in the central nervous system. (A) Spongiform degeneration in human diseases. Left to right, CJD prion plaque surrounded by vacuoles¹, counterstained with hematoxylin and eosin; CJD cerebral cortex², counterstained with hematoxylin and eosin; kuru cerebral cortex², counterstained with hematoxylin and eosin; and AD medial temporal lobe³, counterstained with hematoxylin and eosin. (B) Spongiform degeneration in rodents. Left to right, brainstem from mouse infected with FrCasE retrovirus⁴, immunostained with anti-FrCasE surface glycoprotein; cortex from Mgrn1 null (Mgrn1^md-nc/Mgrn1^md-nc) mouse⁵, immunostained with anti-glial fibrillary acidic protein; cortex from mahogany (Atrn^mg3J/Atrn^mg3J) mouse⁵, immunostained with anti-glial fibrillary acidic protein; and EM of a brainstem vacuole from mahogany (Atrn^mg3J/Atrn^mg3J) mouse⁵. All images reprinted with permission: ¹Reprinted from Lancet Neurology , copyright ©2005, with permission from Elsevier. ²Reprinted from the American Journal of Pathology , copyright ©1972, with permission from the American Society for Investigative Pathology. ³Reprinted from Archives of Neurology , copyright ©1987, with permission from the American Medical Association. All Rights reserved. ⁴Reprinted from the Journal of Biological Chemistry , copyright ©2004, with permission from the American Society for Biochemistry and Molecular Biology. ⁵Reprinted from Science , copyright ©2003, with permission from AAAS.

Fig. 2

Pathways by which Mgrn1-mediated ubiquitination could modulate melanocortin receptor regulation of pigment production and energy metabolism. (A) Mc1r signaling in hair follicle melanocytes regulates coat color. Activation of Mc1r by the ligand α-MSH results in production of the black pigment eumelanin, while suppression of Mc1r by the inverse agonist Agouti promotes the production of the yellow pigment pheomelanin. Mgrn1 may ubiquitinate either Mc1r or a downstream target, complementing Agouti signaling in non-mutant mice. Reduction or loss of Mgrn1-mediated ubiquitination in Mgrn1^md-nc mice would then stimulate production of eumelanin, producing a darker coat. (B) Mc3r and Mc4r signaling in hypothalamic neurons modulates insulin sensitivity, regulating energy homeostasis and body mass. Receptor activation by α-MSH increases insulin sensitivity, promoting leaner body mass, and receptor inhibition by AgRP decreases insulin sensitivity, promoting obesity. In wild-type mice, Mgrn1-mediated ubiquitination of possibly either the receptors or a downstream target could modulate melanocortin signaling in hypothalamic neurons, while in Mgrn1 null mice, a reduction or loss of Mgrn1 activity could then alter energy homeostasis. The role, if any, of Atrn in hypothalamic melanocortin signaling is unclear, although Atrn may regulate neuronal survival via an unknown pathway, which could be modulated by Mgrn1-mediated ubiquitination.

Fig. 3

Potential mechanisms by which impaired proteasome function and increased oxidative stress in spongiform encephalopathies could result in cell death. Impairment of the proteasome by protein aggregates, perturbations in ubiquitin signaling, mitochondrial dysfunction and/or increased cellular ROS can result in increases in proteasome substrates and protein aggregates, alterations in ubiquitination, and apoptotic and/or autophagic cell death via mitochondrial dysfunction and prolonged or aberrant activation of autophagy. Impairment of mitochondrial function by loss of Mgrn1 or attractin signaling, proteasomal dysfunction, or increased cellular ROS can activate apoptosis, increase cellular ROS levels, and inhibit the activity of the proteasome. Increased oxidative stress can promote protein aggregation, which can inhibit the proteasome and activate autophagy, impair the functions of both the mitochondria and the proteasome, and activate apoptosis.

Fig. 4

Potential mechanisms by which dysfunction of ubiquitin-mediated endosome-to-lysosome trafficking in spongiform disorders results in abnormal intracellular signaling, attenuation of lysosomal protein degradation, and impairment of autophagy. Exogenous PrP^Sc and ligand-bound receptors enter the cell via the endocytic pathway. Receptor signaling is modulated by lysosomal degradation, which is dependent upon correct ESCRT-mediated sorting of the receptors. PrP^C trafficking is disrupted by PrP^Sc, which can mediate the conversion of endogenous PrP^C into PrP^Sc in the MVB or other endocytic compartment and accumulates in the MVB/late endosome. Infection of a cell with retroviruses results in the production of viral gag proteins, which hijack the ESCRT sorting machinery to aid in viral budding at the MVB or at the plasma membrane (not shown). Viruses and PrP in the MVB can be released from the cell via the exosome pathway. Loss of Mgrn1-mediated ubiquitination and viral gag proteins disrupt normal ESCRT sorting of cell surface receptors, which interferes with receptor degradation by the lysosome, potentiating receptor intracellular signaling. Dysfunction of both the ESCRT sorting machinery and the lysosome impair degradation of cellular proteins by autophagy.