For a long time, PLS3 (plastin 3, also known as T-plastin or fimbrin) has been considered a rather inconspicuous protein, involved in F-actin-binding and -bundling. However, in recent years, a plethora of discoveries have turned PLS3 into a highly interesting protein involved in many cellular processes, signaling pathways, and diseases. PLS3 is localized on the X-chromosome, but shows sex-specific, inter-individual and tissue-specific expression variability pointing towards skewed X-inactivation. PLS3 is expressed in all solid tissues but usually not in hematopoietic cells. When escaping X-inactivation, PLS3 triggers a plethora of different types of cancers. Elevated PLS3 levels are considered a prognostic biomarker for cancer and refractory response to therapies. When it is knocked out or mutated in humans and mice, it causes osteoporosis with bone fractures; it is the only protein involved in actin dynamics responsible for osteoporosis. Instead, when PLS3 is upregulated, it acts as a highly protective SMN-independent modifier in spinal muscular atrophy (SMA). Here, it seems to counteract reduced F-actin levels by restoring impaired endocytosis and disturbed calcium homeostasis caused by reduced SMN levels. In contrast, an upregulation of PLS3 on wild-type level might cause osteoarthritis. This emphasizes that the amount of PLS3 in our cells must be precisely balanced; both too much and too little can be detrimental. Actin-dynamics, regulated by PLS3 among others, are crucial in a lot of cellular processes including endocytosis, cell migration, axonal growth, neurotransmission, translation, and others. Also, PLS3 levels influence the infection with different bacteria, mycosis, and other pathogens.

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.