Braun RJ, Sommer C, Leibiger C, Gentier RJ, Dumit VI, Paduch K, Eisenberg T, Habernig L, Trausinger G, Magnes C, Pieber T, Sinner F, Dengjel J, van Leeuwen FW, Kroemer G, Madeo F. Accumulation of Basic Amino Acids at Mitochondria Dictates the Cytotoxicity of Aberrant Ubiquitin. Cell Rep. 2015 Mar 3; PubMed.
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University of Barcelona, Bellvitge University Hospital
UBB+1 is translated from an aberrant mRNA encoding a +1 frameshift protein in which the C-terminal glycine residue of ubiquitin B, which is required for ubiquitination, is replaced by an extension of 20 amino acids. This causes in a loss of function when compared with the normal ubiquitin B (UBB). UBB+1 is expressed in neurons containing neurofibrillary tangles in Alzheimer’s disease (AD) and other tauopathies. Early studies showed that UBB+1 compromised ubiquitin-like function and blocked the ubiquitin-proteasome system. Later on, UBB+1 was found to be toxic and eventually to be an inducer of cell death in several settings. Mitochondria acted as pivotal targets. In the present study, Braun et al. show that UBB+1 alters mitochondrial function and associates with increased oxidative stress in the mitochondria. They identify other molecules involved. Furthermore, they link deleterious effects to accumulation of the amino acids arginine, ornithine, and lysine in the mitochondria as a result of UBB+1-related dysfunction. This elegant study implicates, for the first time, abnormal localization of selected amino acids in the mitochondria as mediators of cell dysfunction in AD.
McGill University
Van Leeuwen’s discovery of Ubiquitin +1 (UBB+1) resulting in a +1 frameshift protein with 20 additional C-terminal amino acids on ubiquitin, suggested that the accumulation of misfolded proteins in Alzheimer disease neurons may be due to impaired proteasomal degradation. Here, Braun and colleagues use the exquisite power of yeast genetics to confirm the impairment of the ubiquitin-proteasome system (UPS) by UBB+1 and further identify a mitochondria-associated pathway responsible for the cytotoxic role of UBB+1. Their paper convincingly demonstrates that the toxicity of UBB+1 in yeast is associated with the accumulation of basic amino acids arginine, ornithine, and lysine and that depletion of arginine and ornithine biosynthetic enzymes Arg5,6 and Arg8 rescued UBB+1-mediated cytotoxicity. The involvement of the ubiquitin-proteasomal system (UPS) was demonstrated by showing that Vms1 relieved UBB+1 mitochondrial damage and returned the levels of the three basic amino acids to normal. Vms1 is a cofactor of that AAA-ATPase Cdc48 (p97 or VCP in mammals) that regulates mitochondrial associated protein degradation by the proteasome. Furthermore, by immunohistochemistry the paper shows a co-localization of aberrant tau with VMS1 and VMS1 with UBB+1 in AD brains. The authors conclude that “VMS-1-dependent mitochondrial quality control might retard the Alzheimer disease-associated neuronal dysfunction, which is elicited by the accumulation of both aberrant Tau and UBB+1.”
Yeast provide an elegant system to allow clear identification of pathways induced by aberrant proteins, such as UBB+1. However, the extension of the results to the mammals and to complex diseases such as Alzheimer's will require much more work. The first questions that I would raise are, how does the frameshift UBB+1 arise in the first place and is it unique in Alzheimer disease neurons? A quick PubMed search revealed papers indicating that APP+1 also occurs (Fischer et al., 2006), suggesting the deregulation of basic gene expression mechanisms in Alzheimer disease. If this is the case, there are likely to be other frameshifted proteins and the correction of one defect will not be sufficient to normalize the neurons. Second, it would be essential to confirm that the pathway occurs in neurons, the cell type primarily affected in AD. The co-localization of aberrant tau/VMS1 and UBB+1/VMS1 shown in this paper is one step in this direction and indicates that all proteins involved in the pathway may be co-expressed in neurons affected by Alzheimer's. It should also be determined whether the AD neurons accumulate basic amino acids and whether the levels of VMS1 or p97/VCP are decreased in AD and thus contributing to UBB+1 neurotoxicity. It would be expected that only certain neurons would express UBB+1 if UBB+1 at the core of neurotoxicity since AD pathology is restricted to some neurons.
References:
Fischer DF, Hol EM, Hobo B, Van Leeuwen FW. Alzheimer-associated APP+1 transgenic mice: frameshift beta-amyloid precursor protein is secreted in cerebrospinal fluid without inducing neuropathology. Neurobiol Aging. 2006 Oct;27(10):1445-50. PubMed.
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