Reversible induction of TDP-43 granules in cortical neurons after traumatic injury

The role of liquid–liquid phase separation in aggregation of the TDP-43 low-complexity domain

“…It is likely that the reported recruitment of TDP-43 to cytoplasmic stress granules in vivo (61,62) may involve similar self-association of TDP-43 molecules, thus triggering robust LLPS-mediated fibrillation. Indeed, the notion that LLPS may mediate formation of pathological aggregates of TDP-43 in neurodegenerative diseases is supported by recent observations that TDP-43 aggregates appear to localize to stress granules in Drosophila and mouse models of traumatic brain injury (63,64). Consistent with these findings, our data suggest that LLPS plays a direct role in facilitating aggregation of the TDP-43 LCD, likely by providing an environment of increased local concentration of the protein.…”

Multiplexed chemogenetics in astrocytes and motoneurons restore blood–spinal cord barrier in ALS

“…We set out to investigate the extent and progression of BSCB disruption in four murine ALS models characterized by distinct genetic mutations and different degrees of phenotype severity and progression rate. In particular, we considered the high-copy SOD1 G93A line, together with the FUS Δ NLS/+ ( Scekic-Zahirovic et al, 2017 ), the TDP-43 G298S ( Wiesner et al, 2018 ), and Tbk1 heterozygous knockout ( Tbk1 +/− [ Brenner et al, 2019 ]) lines. In each ALS mouse strain, we investigated three time points at which critical pathological milestones were reached: (i) high-copy SOD1 G93A mice were studied at P20 (appearance of ER stress and misfolded SOD1 buildup; Saxena et al, 2013 ), P50 (denervation of highly vulnerable fast fatigable MN; Pun et al, 2006 ), and P80 (appearance of overt neurological signs; Boillée et al, 2006 ; Ouali Alami et al, 2018 ); (ii) FUS Δ NLS/+ mice were studied at P150 (before appearance of neurological signs and denervation), P270 (appearance of denervation and clasping), and P450 (more advanced neurological signs; Scekic-Zahirovic et al, 2017 ); (iii) TDP-43 G298S mice were studied at P150 (appearance of substantial neurological abnormalities; Wiesner et al, 2018 ), P360 (plateau of neurological dysfunction), and P510 (later stage in neurological dysfunction; subtle neurological abnormalities are present from the earliest time point but start worsening at around P150 with a plateau at around P250; Wiesner et al, 2018 ); and (iv) Tbk1 +/− mice were used as a reference line for ALS disease at P270 and P450, when they showed lack of motor symptoms, weight loss, or premature death ( Brenner et al, 2019 ).…”

“…1404. The following strains of transgenic mice were used: B6SJL-Tg(SOD1*G93A)1Gur/J (high-copy, henceforth SOD1 G93A ) and B6.Cg-Tg(SOD1)2Gur/J (henceforth WT-SOD1) mice were obtained from Jackson laboratories; B6N.129S6(B6)-Chattm2(cre)Lowl/J (henceforth ChAT-Cre ) were a kind gift from Pico Caroni (FMI); C57BL/6NCrl-FUS( Δ NLS) (henceforth FUS ( Δ NLS+/−) ) were obtained from Luc Dupuis (INSERM; [ Scekic-Zahirovic et al, 2016 ]) and bred locally; B6SJL/F1-TDP-43(G298S) (henceforth TDP-43 (G298S) ) were a kind gift from Phil Wong (Johns Hopkins School of Medicine [ Wiesner et al, 2018 ]); and B6.129P2-Tbk1tm1Aki (henceforth Tbk1 +/− ) were a kind gift from Jochen Weishaupt (Ulm University, Ulm; [ Brenner et al, 2019 ]). To generate SOD1 G93A /ChAT-Cre double-transgenic mice, SOD1 G93A+ male mice were crossed with ChAT-Cre +/+ female mice, and the double-positive male mice in the F1 were used for the experiments.…”

TDP-43 and RNA form amyloid-like myo-granules in regenerating muscle

“…Moreover, the seeding of TDP-43 aggregates by TDP-43 oligomers may also occur in neurons since reversible cytoplasmic TDP-43 accumulation occurs in models of acute neuronal injury in vivo (e.g. axotomy or traumatic brain injury) 34, 35 . TDP-43 aggregates are also frequently observed on autopsy in neurologically normal elderly individuals 36 .…”