TARDBP and amyotrophic lateral sclerosis: Such a proposal however leaves many unanswered questions, including: the mechanism by which the Thr175 residue is initially phosphorylated; how pThr175 tau leads to the activation of GSK3β; whether pThr231 tau is necessary and sufficient to induce neuronal dysfunction and death, or whether additional tau protein pathological phosphorylation is needed; and what (if any) role for the co-existent TDP-43 pathology of ALS-FTSD is also necessary to drive the phenomenological aspects of pThr175 tau-mediated tauopathy.