Simulating the Growth of TATA-Box Binding Protein-Associated Factor 15 Inclusions in Neuron Soma.

To the best of the author's knowledge, this paper presents the first attempt to develop a mathematical model of the formation and growth of inclusions containing misfolded TATA-box binding protein associated factor 15 (TAF15). It has recently been shown that TAF15 inclusions are involved in approximately 10% of cases of frontotemporal lobar degeneration (FTLD). FTLD is the second most common neurodegenerative disease after Alzheimer's disease (AD). It is characterized by a progressive loss of personality, behavioral changes, and a decline in language skills due to the degeneration of the frontal and anterior temporal lobes. The model simulates TAF15 monomer production, nucleation and autocatalytic growth of free TAF15 aggregates, and their deposition into TAF15 inclusions. The accuracy of the numerical solution of the model equations is validated by comparing it with analytical solutions available for limiting cases. Physiologically relevant parameter values were used to predict TAF15 inclusion growth. It is shown that the growth of TAF15 inclusions is influenced by two opposing mechanisms: the rate at which free TAF15 aggregates are deposited into inclusions and the rate of autocatalytic production of free TAF15 aggregates from monomers. A low deposition rate slows inclusion growth, while a high deposition rate hinders the autocatalytic production of new aggregates, thus also slowing inclusion growth. Consequently, the rate of inclusion growth is maximized at an intermediate deposition rate of free TAF15 aggregates into TAF15 inclusions.

Kuznetsov AV 《-》

TAF15 amyloid filaments in frontotemporal lobar degeneration.

Tetter S ，Arseni D ，Murzin AG ，Buhidma Y ，Peak-Chew SY ，Garringer HJ ，Newell KL ，Vidal R ，Apostolova LG ，Lashley T ，Ghetti B ，Ryskeldi-Falcon B ... -  《-》

Nuclear carrier and RNA-binding proteins in frontotemporal lobar degeneration associated with fused in sarcoma (FUS) pathological changes.

We aimed to investigate the role of the nuclear carrier and binding proteins, transportin 1 (TRN1) and transportin 2 (TRN2), TATA-binding protein-associated factor 15 (TAF15) and Ewing's sarcoma protein (EWS) in inclusion body formation in cases of frontotemporal lobar degeneration (FTLD) associated with fused in sarcoma protein (FTLD-FUS). Eight cases of FTLD-FUS (five cases of atypical FTLD-U, two of neuronal intermediate filament inclusion body disease and one of basophilic inclusion body disease) were immunostained for FUS, TRN1, TRN2, TAF15 and EWS. Ten cases of FTLD associated with TDP-43 inclusions served as reference cases. The inclusion bodies in FTLD-FUS contained TRN1 and TAF15 and, to a lesser extent, EWS, but not TRN2. The patterns of immunostaining for TRN1 and TAF15 were very similar to that of FUS. None of these proteins was associated with tau or TDP-43 aggregations in FTLD. Data suggest that FUS, TRN1 and TAF15 may participate in a functional pathway in an interdependent way, and imply that the function of TDP-43 may not necessarily be in parallel with, or complementary to, that of FUS, despite each protein sharing many similar structural elements.

Davidson YS ，Robinson AC ，Hu Q ，Mishra M ，Baborie A ，Jaros E ，Perry RH ，Cairns NJ ，Richardson A ，Gerhard A ，Neary D ，Snowden JS ，Bigio EH ，Mann DM ... -  《-》

FET proteins TAF15 and EWS are selective markers that distinguish FTLD with FUS pathology from amyotrophic lateral sclerosis with FUS mutations.

Neumann M ，Bentmann E ，Dormann D ，Jawaid A ，DeJesus-Hernandez M ，Ansorge O ，Roeber S ，Kretzschmar HA ，Munoz DG ，Kusaka H ，Yokota O ，Ang LC ，Bilbao J ，Rademakers R ，Haass C ，Mackenzie IR ... -  《-》

Transportin 1 accumulates specifically with FET proteins but no other transportin cargos in FTLD-FUS and is absent in FUS inclusions in ALS with FUS mutations.

Neumann M ，Valori CF ，Ansorge O ，Kretzschmar HA ，Munoz DG ，Kusaka H ，Yokota O ，Ishihara K ，Ang LC ，Bilbao JM ，Mackenzie IR ... -  《-》