John D. Papatriantafyllou, Greece
Medical Center of Athens Memory Disorders Clinic and Day Care Center for 3rd Age 'IASIS'Author Of 1 Presentation
VACUOLAR TAUOPATHY: A NOVEL HEREDITARY FRONTOTEMPORAL DEMENTIA ASSOCIATED WITH LOSS OF VCP DISAGGREGASE ACTIVITY
Abstract
Aims
Rare genetic causes of human disease have the potential to reveal mechanistic insights into sporadic disease. Identifying novel genetic forms of tauopathy and understanding the pathophysiologic mechanisms that lead to neurofibrillary degeneration may lead to novel insights and perhaps novel therapeutic anti-tau targets.
Methods
Genetic sequencing, clinical phenotyping, neuropathology and radiologic studies were used to define the clinicopathologic features of disease. Recombinant protein biochemistry, cell culture models, and mutant knock-in mice were used to study pathophysiologic mechanisms.
Results
Two kindred were identified with autosomal dominant behavioral variant frontotemporal dementia. Neuropathologic and radiologic studies indicated that neurodegeneration was associated with neurofibrillary tangles. In addition, there was abnormal vacuolization of neocortical neurons. These "Vacuolar Tauopathy" cases were assocaited with a novel VCP (Vaolsin-Containing Protein) mutation, distinct from mutations that cause TDP-43 proteinopathy. Recombinant protein biochemistry demonstrated that the vacuolar tauopathy mutation was associated with a partial loss of function. Moreover, recombinant VCP appeared to exhibit disaggregase activity against pathologic tau and mutant VCP expression was associated with enhanced tau aggregation in both cellular and animal models. Ongoing studies suggest that there are mechanistic differences between VCP mutations that cause tauopathy versus TDP-43 proteinopathy.
Conclusions
Vacuolar Tauopathy is a novel autosomal dominant tauopathy associated with a hypomorph VCP mutation which impairs disaggregase activity. Different mutations of the same gene (VCP) can lead to different underlying neuropathologies (tau versus TDP-43) but the same clinical presentation (FTD), a remarkable instance of allelic heterogeneity. These results suggest that VCP may be a novel target for the treatment of tauopathies.