Zhao Y, Tseng IC, Heyser CJ, Rockenstein E, Mante M, Adame A, Zheng Q, Huang T, Wang X, Arslan PE, Chakrabarty P, Wu C, Bu G, Mobley WC, Zhang YW, St George-Hyslop P, Masliah E, Fraser P, Xu H. Appoptosin-Mediated Caspase Cleavage of Tau Contributes to Progressive Supranuclear Palsy Pathogenesis. Neuron. 2015 Sep 2;87(5):963-75. PubMed. Correction.

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  1. Progressive supranuclear palsy (PSP) is a debilitating and deadly neurodegenerative disorder. It is neuropathologically defined by aggregation of the microtubule-associated protein tau in the somata of neurons, oligodendrocytes, and astrocytes. The etiopathogenesis of the disease remains unresolved. Homozygosity for the H1 haplotype of the MAPT gene has been identified as a strong genetic risk factor for PSP. A recent genome-wide association study has confirmed this association and identified three additional risk loci, i.e., STX6, EIF2AK3, and MOBP (Höglinger et al., 2011). The MAPT polymorphism appears to result in altered expression of the protein tau, causing increased aggregation of this protein. In contrast, the pathogenic mechanism of the STX6, EIF2AK3, and MOBP polymorphism has remained unresolved until recently. The association of a genetic polymorphism (T allele of rs1768208) at MOBP (myelin-associated oligodendrocyte basic protein) was particularly puzzling since this gene encodes for an abundantly expressed myelin-constituting protein of the CNS (Yamamoto et al., 1994). 

    Very interestingly, the rs1768208 MOBP risk polymorphism has also been found to increase risk for the primary tauopathy corticobasal degeneration (CBD, Kouri et al., 2015) and for late-onset Alzheimer’s disease of APOE ε4-positive cases (Liu et al., 2012). Furthermore, the rs1768208 MOBP risk polymorphism has a negative prognostic value in the behavioral-variant frontotemporal dementia. Carriers of the risk (T) allele exhibit more severe white-matter degeneration and shorter disease duration. This particularly applies to autopsy-confirmed patients with tauopathies, but not to cases displaying TDP-43 proteinopathies (Irwin et al., 2014). Taken together, these genetic associations have pointed to a relevant role of the rs1768208 MOBP risk polymorphism in neurodegenerative tauopathies.

    In a first attempt to understand the biological mechanism behind this association, the effect of variability at rs1768208 on gene expression in human brains has been studied (Höglinger et al., 2011). SNPs located in or near MOBP showed some moderate effect on MOBP expression. However, a highly significant effect was discovered for SLC25A38 expression, which lies 70 kb from MOBP (Höglinger et al., 2011).

    In 2012, Zhang et al. identified the SLC25A38 gene product as a β-amyloid precursor protein (APP)-interacting protein, designated as appoptosin, which is upregulated in brains from patients with Alzheimer's disease. They found appoptosin to be a pro-apoptotic protein that induces caspase-3-dependent apoptosis (Zhang et al., 2012). 

    Here, the same group reports a high frequency of the T allele and increased levels of the pro-apoptotic protein appoptosin in PSP. They show that increased expression of appoptosin correlates with activated caspase-3 and caspase-cleaved tau levels, tau aggregation, and synaptic dysfunction. In contrast, appoptosin deficiency reduced tau cleavage and aggregation. They also found increased appoptosin and caspase-3-cleaved tau in brains of patients with Alzheimer’s disease and FTLD-Tau.

    According to the authors, about 75 percent of PSP patients carry at least one copy of the T allele of rs1768208 and 25 percent do not (they carry the C allele). As the authors convincingly show, the T but not the C allele increases activity of appoptosin, which activates caspase-3, which in turn cleaves tau. In patients carrying the C allele, however, the same pathological mechanism might apply as in patients with the T allele, and appoptosin might be activated by environmental factors such as neurotoxins and stress. It will be interesting to see whether the most severe manifestations of PSP are found among patients carrying the T allele in the homozygous state, since environmental factors might further increase appoptosin activity.

    These exciting findings are a major step forward, since they resolve the previously enigmatic genetic association of variation at the MOBP/SLC25A38 locus with the neurobiology of tauopathies. Furthermore, appoptosin might be the missing link between amyloid-β and tau in Alzheimer’s disease, which has been desperately sought for a long time.

    This paper is adrenalin! Don’t miss it.

    References:

    Höglinger GU, Melhem NM, Dickson DW, Sleiman PM, Wang LS, Klei L, Rademakers R, de Silva R, Litvan I, Riley DE, van Swieten JC, Heutink P, Wszolek ZK, Uitti RJ, Vandrovcova J, Hurtig HI, Gross RG, Maetzler W, Goldwurm S, Tolosa E, Borroni B, Pastor P, PSP Genetics Study Group, Cantwell LB, Han MR, Dillman A, van der Brug MP, Gibbs JR, Cookson MR, Hernandez DG, Singleton AB, Farrer MJ, Yu CE, Golbe LI, Revesz T, Hardy J, Lees AJ, Devlin B, Hakonarson H, Müller U, Schellenberg GD. Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy. Nat Genet. 2011 Jun 19;43(7):699-705. PubMed.

    Irwin DJ, McMillan CT, Suh E, Powers J, Rascovsky K, Wood EM, Toledo JB, Arnold SE, Lee VM, Van Deerlin VM, Trojanowski JQ, Grossman M. Myelin oligodendrocyte basic protein and prognosis in behavioral-variant frontotemporal dementia. Neurology. 2014 Aug 5;83(6):502-9. Epub 2014 Jul 3 PubMed.

    Kouri N, Ross OA, Dombroski B, Younkin CS, Serie DJ, Soto-Ortolaza A, Baker M, Finch NC, Yoon H, Kim J, Fujioka S, McLean CA, Ghetti B, Spina S, Cantwell LB, Farlow MR, Grafman J, Huey ED, Ryung Han M, Beecher S, Geller ET, Kretzschmar HA, Roeber S, Gearing M, Juncos JL, Vonsattel JP, Van Deerlin VM, Grossman M, Hurtig HI, Gross RG, Arnold SE, Trojanowski JQ, Lee VM, Wenning GK, White CL, Höglinger GU, Müller U, Devlin B, Golbe LI, Crook J, Parisi JE, Boeve BF, Josephs KA, Wszolek ZK, Uitti RJ, Graff-Radford NR, Litvan I, Younkin SG, Wang LS, Ertekin-Taner N, Rademakers R, Hakonarsen H, Schellenberg GD, Dickson DW. Genome-wide association study of corticobasal degeneration identifies risk variants shared with progressive supranuclear palsy. Nat Commun. 2015 Jun 16;6:7247. PubMed.

    Liu QY, Yu JT, Miao D, Ma XY, Wang HF, Wang W, Tan L. An exploratory study on STX6, MOBP, MAPT, and EIF2AK3 and late-onset Alzheimer's disease. Neurobiol Aging. 2013 May;34(5):1519.e13-7. Epub 2012 Oct 30 PubMed.

    Yamamoto Y, Mizuno R, Nishimura T, Ogawa Y, Yoshikawa H, Fujimura H, Adachi E, Kishimoto T, Yanagihara T, Sakoda S. Cloning and expression of myelin-associated oligodendrocytic basic protein. A novel basic protein constituting the central nervous system myelin. J Biol Chem. 1994 Dec 16;269(50):31725-30. PubMed.

    Zhang H, Zhang YW, Chen Y, Huang X, Zhou F, Wang W, Xian B, Zhang X, Masliah E, Chen Q, Han JD, Bu G, Reed JC, Liao FF, Chen YG, Xu H. Appoptosin is a novel pro-apoptotic protein and mediates cell death in neurodegeneration. J Neurosci. 2012 Oct 31;32(44):15565-76. PubMed.

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