Department of Neurology, Baylor College of Medicine, Houston, Texas, USA.
Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, Texas, USA.
JCI Insight. 2022 Apr 22;7(8):e154442. doi: 10.1172/jci.insight.154442.
Spinocerebellar ataxia type 1 (SCA1) is an adult-onset neurodegenerative disorder. As disease progresses, motor neurons are affected, and their dysfunction contributes toward the inability to maintain proper respiratory function, a major driving force for premature death in SCA1. To investigate the isolated role of motor neurons in SCA1, we created a conditional SCA1 (cSCA1) mouse model. This model suppresses expression of the pathogenic SCA1 allele with a floxed stop cassette. cSCA1 mice crossed to a ubiquitous Cre line recapitulate all the major features of the original SCA1 mouse model; however, they took twice as long to develop. We found that the cSCA1 mice produced less than half of the pathogenic protein compared with the unmodified SCA1 mice at 3 weeks of age. In contrast, restricted expression of the pathogenic SCA1 allele in motor neurons only led to a decreased distance traveled of mice in the open field assay and did not affect body weight or survival. We conclude that a 50% or greater reduction of the mutant protein has a dramatic effect on disease onset and progression; furthermore, we conclude that expression of polyglutamine-expanded ATXN1 at this level specifically in motor neurons is not sufficient to cause premature lethality.
脊髓小脑共济失调 1 型（SCA1）是一种成年发病的神经退行性疾病。随着疾病的进展，运动神经元受到影响，其功能障碍导致无法维持正常的呼吸功能，这是 SCA1 患者过早死亡的主要驱动因素。为了研究运动神经元在 SCA1 中的孤立作用，我们创建了条件性 SCA1（cSCA1）小鼠模型。该模型通过 floxed 终止盒抑制致病 SCA1 等位基因的表达。cSCA1 小鼠与普遍存在的 Cre 线杂交可重现原始 SCA1 小鼠模型的所有主要特征；然而，它们需要两倍的时间来发展。我们发现，与未修饰的 SCA1 小鼠相比，cSCA1 小鼠在 3 周龄时产生的致病蛋白不到一半。相比之下，仅在运动神经元中限制表达致病 SCA1 等位基因，导致小鼠在旷场试验中行进的距离缩短，但不影响体重或存活。我们得出的结论是，突变蛋白减少 50%或更多对疾病的发病和进展有显著影响；此外，我们得出的结论是，在这种水平下，仅在运动神经元中表达多聚谷氨酰胺扩展的 ATXN1 不足以导致过早死亡。
