Many
neurodegenerative disorders share common pathogenic pathways such as endocytic defects, Ca2+ misregulation and defects in actin dynamics. Factors acting on these shared pathways are highly interesting as a therapeutic target.
Plastin 3 (PLS3), a proven protective modifier of
spinal muscular atrophy across species, is a remarkable example of the former, and thereby offers high potential as a cross-disease modifier. Importantly, PLS3 has been linked to numerous
proteins associated with various
neurodegenerative diseases. Among them, PLS3 directly interacts with
calcineurin like EF-hand
protein 1 (
CHP1), whose loss-of-function results in
ataxia. In this study, we aimed to determine whether PLS3 is a cross-disease modifier for
ataxia caused by
Chp1 mutation in mice. For this purpose, we generated
Chp1 mutant mice, named vacillator mice, overexpressing a PLS3 transgene. Here, we show that PLS3 overexpression (OE) delays the ataxic phenotype of the vacillator mice at an early but not later disease stage. Furthermore, we demonstrated that PLS3 OE ameliorates axon
hypertrophy and axonal swellings in Purkinje neurons thereby slowing down neurodegeneration. Mechanistically, we found that PLS3 OE in the cerebellum shows a trend of increased membrane targeting and/or expression of Na+/H+ exchanger (NHE1), an important
CHP1 binding partner and a causative gene for
ataxia, when mutated in humans and mice. This data supports the hypothesis that PLS3 is a cross-
disease genetic modifier for CHP1-causing
ataxia and
spinal muscular atrophy.