Conditional ATXN2L-Null in Adult Frontal Cortex CamK2a+ Neurons Does Not Cause Cell Death, but Restricts Spontaneous Mobility, and Affects the Alternative Splicing Pathway

Ataxin-2-like (ATXN2L) protein is required to survive embryonic development, as documented in mice with constitutive absence of ATXN2L Lsm, LsmAD and PAM2 domains, due to knockout (KO) of exons 5-8 with frameshift. Its less abundant paralog Ataxin-2 (ATXN2) has an extended N-terminus, where a polyglutamine domain is prone to expansions, which mediate vulnerability to the polygenic adult motor neuron disease ALS (Amyotrophic Lateral Sclerosis), or cause the monogenic neurodegenerative processes of Spinocerebellar Ataxia type 2 (SCA2), depending on larger mutation sizes. Here, we elucidated the physiological function of ATXN2L by deleting the LsmAD and PAM2 motif, via loxP-mediated KO of exons 10-17 with frameshift. Crossing heterozygous floxed mice with constitutive Cre-deleter animals confirmed embryonic lethality among offspring. Crossing with CamK2a-CreERT2 mice and injecting tamoxifen for conditional deletion achieved chimeric ATXN2L absence in CamK2a-positive frontal cortex neurons and resulted in reductions of spontaneous horizontal movement. Global proteome profiling of frontal cortex homogenate found ATXN2L levels decreased to 75%, and dysregulations enriched in the alternative splicing pathway. Nuclear proteins with Sm domains are critical to perform splicing, so our data suggest that the Like-Sm (Lsm, LsmAD) domains in ATXN2L serve a role in splice regulation, despite its perinuclear location.