Mutant PFN1 causes ALS phenotypes and progressive motor neuron degeneration in mice by a gain of toxicity

被引:77
|
作者
Yang, Chunxing [1 ]
Danielson, Eric W. [2 ]
Qiao, Tao [1 ]
Metterville, Jake [2 ]
Brown, Robert H., Jr. [2 ]
Landers, John E. [2 ]
Xu, Zuoshang [1 ,3 ,4 ]
机构
[1] Univ Massachusetts, Sch Med, Dept Biochem & Mol Pharmacol, Worcester, MA 01605 USA
[2] Univ Massachusetts, Sch Med, Dept Neurol, Worcester, MA 01605 USA
[3] Univ Massachusetts, Sch Med, Dept Cell Biol, Worcester, MA 01605 USA
[4] Univ Massachusetts, Sch Med, Neurosci Program, Worcester, MA 01605 USA
关键词
neurodegeneration; motor neuron disease; muscle atrophy; denervation; proteostasis; AMYOTROPHIC-LATERAL-SCLEROSIS; SOD1-G93A MOUSE MODEL; ANTERIOR HORN CELLS; TRANSGENIC MICE; PROTEIN AGGREGATION; PROFILIN; INCLUSION-BODY; DISEASE; SOD1; MUTATION;
D O I
10.1073/pnas.1605964113
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Mutations in the profilin 1 (PFN1) gene cause amyotrophic lateral sclerosis (ALS), a neurodegenerative disease caused by the loss of motor neurons leading to paralysis and eventually death. PFN1 is a small actin-binding protein that promotes formin-based actin polymerization and regulates numerous cellular functions, but how the mutations in PFN1 cause ALS is unclear. To investigate this problem, we have generated transgenic mice expressing either the ALS-associated mutant (C71G) or wild-type protein. Here, we report that mice expressing the mutant, but not the wild-type, protein had relentless progression of motor neuron loss with concomitant progressive muscle weakness ending in paralysis and death. Furthermore, mutant, but not wild-type, PFN1 forms insoluble aggregates, disrupts cytoskeletal structure, and elevates ubiquitin and p62/SQSTM levels in motor neurons. Unexpectedly, the acceleration of motor neuron degeneration precedes the accumulation of mutant PFN1 aggregates. These results suggest that although mutant PFN1 aggregation may contribute to neurodegeneration, it does not trigger its onset. Importantly, these experiments establish a progressive disease model that can contribute toward identifying the mechanisms of ALS pathogenesis and the development of therapeutic treatments.
引用
收藏
页码:E6209 / E6218
页数:10
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