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Disease-specific accumulation of mutant ubiquitin as a marker for proteasomal dysfunction in the brain

DAVID F. FISCHER, ROB A. I. DE VOS^*, RENSKE VAN DIJK, FEMKE M. S. DE VRIJ, EVELIEN A. PROPER, MARC A. F. SONNEMANS, MARIAN C. VERHAGE, JACQUELINE A. SLUIJS, BARBARA HOBO, MOHAMED ZOUAMBIA, ERNST N. H. JANSEN STEUR^*, WOUTER KAMPHORST, ELLY M. HOL and FRED W. VAN LEEUWEN¹

Graduate School for Neurosciences Amsterdam and Netherlands Institute for Brain Research, Amsterdam, The Netherlands;
^* Pathological Laboratory Oost Nederland and Medisch Spectrum Twente, Enschede, The Netherlands;
Rudolf Magnus Institute for Neurosciences, Utrecht Medical Centre, The Netherlands; and
Department of Neuropathology, University Hospital Free University, Amsterdam, The Netherlands

¹Correspondence: Netherlands Institute for Brain Research, Meibergdreef 33, 1105 AZ Amsterdam The Netherlands. E-mail: f.van.leeuwen{at}nih.knaw.nl

Molecular misreading of the ubiquitin-B (UBB) gene results in a dinucleotide deletion in UBB mRNA. The resulting mutant protein, UBB⁺¹, accumulates in the neuropathological hallmarks of Alzheimer disease. In vitro, UBB⁺¹ inhibits proteasomal proteolysis, although it is also an ubiquitin fusion degradation substrate for the proteasome. Using the ligase chain reaction to detect dinucleotide deletions, we report here that UBB⁺¹ transcripts are present in each neurodegenerative disease studied (tauo- and synucleinopathies) and even in control brain samples. In contrast to UBB⁺¹ transcripts, UBB⁺¹ protein accumulation in the ubiquitin-containing neuropathological hallmarks is restricted to the tauopathies such as Pick disease, frontotemporal dementia, progressive supranuclear palsy, and argyrophilic grain disease. Remarkably, UBB⁺¹ protein is not detected in the major forms of synucleinopathies (Lewy body disease and multiple system atrophy). The neurologically intact brain can cope with UBB⁺¹ as lentivirally delivered UBB⁺¹ protein is rapidly degraded in rat hippocampus, whereas the K29,48R mutant of UBB⁺¹, which is not ubiquitinated, is abundantly expressed. The finding that UBB⁺¹ protein only accumulates in tauopathies thus implies that the ubiquitin-proteasome system is impaired specifically in this group of neurodegenerative diseases and not in synucleinopathies and that the presence of UBB⁺¹ protein reports proteasomal dysfunction in the brain.—Fischer, D. F., de Vos, R. A. I., van Dijk, R., De Vrij, F. M. S., Proper, E. A., Sonnemans, M. A. F., Verhage, M. C., Sluijs, J. A., Hobo, B., Zouambia, M., Jansen Steur, E. N. H., Kamphorst, W., Hol, E. M., van Leeuwen, F. W. Disease-specific accumulation of mutant ubiquitin as a marker for proteasomal dysfunction in the brain.

Key Words: tauopathies • synucleinopathies • molecular misreading • UBB⁺¹ • lentivirus

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