Antisense Oligonucleotide Therapy Targeted Against ATXN3 Improves Potassium Channel-Mediated Purkinje Neuron Dysfunction in Spinocerebellar Ataxia Type 3.
Antisense Oligonucleotide Therapy Targeted Against ATXN3 Improves Potassium Channel-Mediated Purkinje Neuron Dysfunction in Spinocerebellar Ataxia Type 3.
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DOI：
10.1007/s12311-020-01179-7
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发表时间：
2021-03
期刊：
影响因子：
--
通讯作者：
McLoughlin HS
中科院分区：
文献类型：
--
作者：
Bushart DD;Zalon AJ;Zhang H;Morrison LM;Guan Y;Paulson HL;Shakkottai VG;McLoughlin HS
脊髓小脑性共济失调3型（SCA3）是第二常见的CAG重复疾病，由ATXN3蛋白中的谷氨酰胺编码扩增引起。SCA3的特征在于脊髓小脑变性，导致进行性运动不协调和早期死亡。以往的研究表明，钾通道功能障碍的基础小脑皮层浦肯野神经元放电SCA3的早期异常。然而，小脑皮质变性在SCA3的人类疾病和小鼠模型中通常是适度的，这增加了小脑功能障碍在SCA3中的作用的不确定性。在这里，我们解决这个问题，通过调查浦肯野神经元的兴奋性SCA3。在早期SCA3小鼠中，我们证实了先前确定的小脑浦肯野神经元兴奋性增加，并将这种兴奋性与两个电压门控钾（KV）通道Kcna6和Kcnc3的转录减少以及运动障碍联系起来。脑室内递送反义寡核苷酸（阿索）以减少突变体ATXN3恢复SCA 3浦肯野神经元的正常兴奋性并挽救Kcna 6和Kcnc 3的转录水平。有趣的是，虽然更广泛的KV通道转录物在晚期SCA3小鼠中显示出降低的水平，但小脑浦肯野神经元生理学没有进一步改变，尽管运动障碍持续恶化。这些结果表明，在SCA3中观察到的进行性运动表型可能并不反映小脑皮质的持续变化，而是小脑内外其他神经元结构的功能障碍。然而，阿索治疗对KV通道表达和神经元兴奋性的早期拯救表明小脑皮质功能障碍对SCA3中的运动功能障碍有意义地贡献。
Spinocerebellar ataxia type 3 (SCA3) is the second-most common CAG repeat disease, caused by a glutamine-encoding expansion in the ATXN3 protein. SCA3 is characterized by spinocerebellar degeneration leading to progressive motor incoordination and early death. Previous studies suggest that potassium channel dysfunction underlies early abnormalities in cerebellar cortical Purkinje neuron firing in SCA3. However, cerebellar cortical degeneration is often modest both in the human disease and mouse models of SCA3, raising uncertainty about the role of cerebellar dysfunction in SCA3. Here we address this question by investigating Purkinje neuron excitability in SCA3. In early stage SCA3 mice, we confirm a previously identified increase in excitability of cerebellar Purkinje neurons and associate this excitability with reduced transcripts of two voltage-gated potassium (KV) channels, Kcna6 and Kcnc3, as well as motor impairment. Intracerebroventricular delivery of antisense oligonucleotides (ASO) to reduce mutant ATXN3 restores normal excitability to SCA3 Purkinje neurons and rescues transcript levels of Kcna6 and Kcnc3. Interestingly, while an even broader range of KV channel transcripts show reduced levels in late-stage SCA3 mice, cerebellar Purkinje neuron physiology was not further altered despite continued worsening of motor impairment. These results suggest the progressive motor phenotype observed in SCA3 may not reflect ongoing changes in the cerebellar cortex but instead dysfunction of other neuronal structures within and beyond the cerebellum. Nevertheless, the early rescue of both KV channel expression and neuronal excitability by ASO treatment suggests that cerebellar cortical dysfunction contributes meaningfully to motor dysfunction in SCA3.
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影响因子：
2.5
作者：
Bushart DD;Shakkottai VG
通讯作者：
Shakkottai VG
影响因子：
14.5
作者：
du Montcel, Sophie Tezenas;Durr, Alexandra;Stevanin, Giovanni
通讯作者：
Stevanin, Giovanni
影响因子：
16.2
作者：
Adelman, JP;Bond, CT;Maylie, J
通讯作者：
Maylie, J
DOI：
10.1016/s0169-328x(96)00120-9
发表时间：
1996-11-01
期刊：
MOLECULAR BRAIN RESEARCH
影响因子：
--
作者：
Laube, G;Roper, J;Veh, RW
通讯作者：
Veh, RW
影响因子：
4.7
作者：
Emir UE;Brent Clark H;Vollmers ML;Eberly LE;Öz G
通讯作者：
Öz G