Charge and redox states modulate granulin—TDP-43 coacervation toward phase separation or aggregation

Protein conformation and biomolecular condensates

“…A prominent example is the phosphorylation and methylation, which increase the saturation concentration of FUS and change the material properties of its condensates ( Monahan et al., 2017 ; Hofweber et al., 2018 ; Qamar et al., 2018 ). Other examples are the activation of the T cell receptor phosphorylation of signaling components on the plasma membrane ( Su et al., 2016 ), the dissolution of several condensates during mitosis by the activity of the tyrosine-phosphorylation-regulated kinase 3 ( Rai et al., 2018 ), and the fine-tuning of condensation or aggregation of a PLD and granulin fragments by the redox state of cysteine residues ( Bhopatkar et al., 2022 ).…”

Distinct neurotoxic TDP-43 fibril polymorphs are generated by heterotypic interactions with α-Synuclein

“…These suggest that isolated PrLD puncta are formed prior to introducing αS, which can be oligomers, protofibrils, or fibrils. Lack of fluorescence recovery after photobleaching recovery on these puncta ( 54 ) indicated they are not droplets. The αS monomers taken up by the cells can potentially interact with monomers, as well as the aggregates of PrLD in the preformed puncta.…”

Progranulin haploinsufficiency mediates cytoplasmic TDP-43 aggregation with lysosomal abnormalities in human microglia

“…In addition, GRN -deficient microglia exhibit extranuclear TDP-43 condensates with lipid droplets in a zebrafish model of traumatic brain injury [ 58 ]. Granulins have been shown to exacerbate TDP-43 toxicity in vivo in Caenorhabditis elegans and mice [ 67 ] and to alter the solubility of TPD-43, thereby modulating its phase separation and aggregation properties [ 68 , 69 ]. The cell model of iMGs, similar to lymphocytes, may reflect the inflammatory state of FTD– GRN, including complement activation, inflammation, and other aging factors, which could result in cytoplasmic TDP-43 accumulation.…”