Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: UMLS:C0004134 (
ataxia
)
15,886
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Many neurodegenerative disorders share common pathogenic pathways such as endocytic defects, Ca
2+
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.
...
PMID:PLS3 Overexpression Delays Ataxia in
Chp1
Mutant Mice. 3160 45
