Additionally, we are grateful for the immense support from
#ALSCanada, @braincanada.bsky.social, #NSERC, #CIHR, and the many facilities @uottawamed.bsky.social and everyone else involved!

This work could not have been done without everyone in the @maximewc.bsky.social lab, all of our colleagues and collaborators, the constructive feedback from the reviewers, and the many discussions at various meetings throughout the years!

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

As #aging is one of the strongest risk factors for neurodegenerative diseases, we hypothesized that the stress of aging depends on effective TDP-43 SUMOylation to protect neurons in the nervous system

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.

We were interested in trying to understand the mechanisms by which cellular stress regulates #TDP43 and how these pathways may contribute to sporadic forms of neurodegeneration including #ALS and #FTD. We hypothesized that #SUMOylation may play a role.

🔬Here’s what we found:

We’re happy to share that our labs first #ALS and #FTD study “A stress-dependent TDP-43 SUMOylation program preserves neuronal function” is now online at Molecular Neurodegeneration! doi.org/10.1186/s130...