Finally we find that SUMOylation is correlated with aging and ALS/FTD in the human brain 🧠 This work has unlocked so many new questions that we are excited to explore!

Surprisingly we found that blocking TDP-43 SUMOylation at K408 in mice 🐭 causes significant #sexdifferences including cognitive and social impairment in female mice whereas male mice show evidence of motor neuron dysfunction in the spinal cord

In neuron cultures 🧫 we find that without SUMOylation at K408, neurons are not able to recover efficiently from cellular stress leading to the accumulation of nuclear TDP-43 recovery bodies

Using #CRISPR 🧬we generated a new knock in #mousemodel 🐁 to block SUMOylation at endogenous K408 allowing us to study what happens to TDP-43 when it can no longer be SUMOylated at this site.

SUMO2/3 is targeted to lysine K408 on TDP-43’s C-terminal domain, directly neighbouring serine residues characteristically phosphorylated in disease. Interestingly this post-translationally modified region is particularly well conserved in vertebrate species.

Indeed, we discovered that TDP-43 is dynamically SUMOylated by SUMO2/3 in the nucleus specifically under stress conditions to aid in protein clearance during recovery from stress.