Conditional ATXN2L-nConditional ATXN2L-null in adult frontal cortex CamK2a+ neurons does not cause cell death, but restricts spontaneous mobility, and affects the alternative splicing pathway

ABSTRACT: 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 CreERT2 mice and injecting tamoxifen for conditional deletion achieved (i) chimeric ATXN2L absence in half of CamK2a-positive frontal cortex neurons upon immunohistochemistry, with (ii) 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.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

SUBMITTER: David Meierhofer  

LAB HEAD: Georg Auburger

PROVIDER: PXD064497 | Pride | 2025-10-27

REPOSITORIES: Pride