FTLD-TDP assemblies seed neoaggregates with subtype-specific features via a prion-like cascade.
FTLD-TDP assemblies seed neoaggregates with subtype-specific features via a prion-like cascade.
复制标题
FTLD-TDP 组装体通过类似朊病毒的级联产生具有亚型特异性特征的新聚集体。
DOI：
10.15252/embr.202153877
复制
发表时间：
2021-12-06
期刊：
影响因子：
7.7
通讯作者：
Polymenidou M
中科院分区：
文献类型：
--
作者：
De Rossi P;Lewis AJ;Furrer J;De Vos L;Demeter T;Zbinden A;Zhong W;Wiersma VI;Scialo C;Weber J;Guo Z;Scaramuzza S;Di Fabrizio M;Böing C;Castaño-Díez D;Al-Amoudi A;Pérez-Berlanga M;Lashley T;Stahlberg H;Polymenidou M
Morphologically distinct TDP‐43 aggregates occur in clinically different FTLD‐TDP subtypes, yet the mechanism of their emergence and contribution to clinical heterogeneity are poorly understood. Several lines of evidence suggest that pathological TDP‐43 follows a prion‐like cascade, but the molecular determinants of this process remain unknown. We use advanced microscopy techniques to compare the seeding properties of pathological FTLD‐TDP‐A and FTLD‐TDP‐C aggregates. Upon inoculation of patient‐derived aggregates in cells, FTLD‐TDP‐A seeds amplify in a template‐dependent fashion, triggering neoaggregation more efficiently than those extracted from FTLD‐TDP‐C patients, correlating with the respective disease progression rates. Neoaggregates are sequentially phosphorylated with N‐to‐C directionality and with subtype‐specific timelines. The resulting FTLD‐TDP‐A neoaggregates are large and contain densely packed fibrils, reminiscent of the pure compacted fibrils present within cytoplasmic inclusions in postmortem brains. In contrast, FTLD‐TDP‐C dystrophic neurites show less dense fibrils mixed with cellular components, and their respective neoaggregates are small, amorphous protein accumulations. These cellular seeding models replicate aspects of the patient pathological diversity and will be a useful tool in the quest for subtype‐specific therapeutics. Pathological TDP‐43 derived from FTLD patient brains triggers de novo aggregation of physiological TDP‐43 in host cells via a prion‐like cascade. Different subtypes of FTLD‐TDP show distinct organization of TDP‐43 aggregates in patient brains, different seeding potencies, neoaggregate structures and C‐terminal serine phosphorylation timelines.
登录
查看更多内容
影响因子：
25
作者：
Chou CC;Zhang Y;Umoh ME;Vaughan SW;Lorenzini I;Liu F;Sayegh M;Donlin-Asp PG;Chen YH;Duong DM;Seyfried NT;Powers MA;Kukar T;Hales CM;Gearing M;Cairns NJ;Boylan KB;Dickson DW;Rademakers R;Zhang YJ;Petrucelli L;Sattler R;Zarnescu DC;Glass JD;Rossoll W
通讯作者：
Rossoll W
影响因子：
4.8
作者：
Babinchak, W. Michael;Haider, Raza;Surewicz, Witold K.
通讯作者：
Surewicz, Witold K.
影响因子：
16.8
作者：
Cao, Qin;Boyer, David R.;Eisenberg, David S.
通讯作者：
Eisenberg, David S.
影响因子：
3
作者：
Kremer, JR;Mastronarde, DN;McIntosh, JR
通讯作者：
McIntosh, JR
影响因子：
4
作者：
Ayala, Youhna M.;Zago, Paola;Baralle, Francisco E.
通讯作者：
Baralle, Francisco E.