Thomas Nguyen

 Introduction. Frontotemporal dementia (FTD) is the major young-onset dementia besides Alzheimer’s disease with an estimated lifetime risk of 1 in 742 and presents clinically as a disturbance in behavior, particularly in intrapersonal conduct or language^1,2. Three major causal gene mutations have been implicated in over 80% of genetic or familial FTD: C9orf72, GRN, and MAPT³. Understanding the mechanisms of the MAPT mutations, specifically N279K and P301L, is imperative if we hope to attenuate the synaptic loss seen in FTD³. Methods. The N279K mutation in iPS cell-derived NPCs was edited using Cas9, then transduced with the pLEX307 vector⁴. A second study investigating the N279K mutation isolated primary human skin fibroblasts from two N279K-confirmed patients, then generated and differentiated iPSC’s for analysis with Western blot⁵. Two studies investigating the P301L mutation used the transgenic mice strain rTg4510 expressing the P301L tau mutation, with the first study additionally using SWATH-MS proteomics to identify alterations in protein expression^6-7. The final study investigating the P301L mutation used FTD patient-derived iPSCs carrying the Tau P301L mutation to generate P301L:Δp35KI isogenic iPSC lines using CRISPR/Cas9 genome editing⁸. Results. Healthy neurons had increased susceptibility to rotenone-induced oxidative stress after co-culture with N279K astrocytes, while N279K NSCs displayed a higher incidence of G3BP- or TIA-1-positive stress granules than control NSCs. Both of these findings suggest that the N279K mutation plays a role in increasing neuronal vulnerability to oxidative stress^4,5. Synthesis of ribosomal protein subunits RPLP0, RPL19, RPL23, and RPS16 were significantly decreased in rTg4510 mice, while AP firing was reduced in the excitatory pyramidal neurons of rTg4510 mice^6,7. Furthermore, P301L iPSCs had a significant reduction in p25 abundance after genetically manipulating human cerebral organoid (from P30L mutated lines) into P301L;Δp35KI, which then caused a similar reduction in total tau levels (p = 0.0029). These findings suggest a role of P301L in the dysregulation of protein synthesis and AP firing through mutant tau accumulation⁸_. Conclusions. N279K astrocytes render neighboring neurons more vulnerable to respiratory stress by disrupting the transport of membrane-bound organelles^4,5. The P301L mutation alters protein synthesis by altering synthesis of specific ribosomal subunit proteins⁶. Pharmacological stabilization of microtubules with Paclitaxel prevented both the structural and functional deficits caused by tau phosphorylation, suggesting a target mechanism for effective therapy in FTD⁷. Development of a therapy that inhibits accumulation of p25 in aberrant Cdk5 activation could attenuate the synaptic atrophy seen in FTD by reducing the level of hyperphosphorylated tau⁸.

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