Graduate Program in Neuroscience, University of British Columbia, Vancouver, British Columbia, Canada.
Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, British Columbia, Canada.
J Neurochem. 2024 Sep;168(9):2671-2689. doi: 10.1111/jnc.16132. Epub 2024 May 21.
Huntington's disease (HD) is a monogenic disorder with autosomal dominant inheritance. In HD patients, neurons in the striatum and cortex degenerate, leading to motor, psychiatric and cognitive disorders. Dysregulated synaptic function and calcium handling are common in many neurodegenerative diseases, including HD. N-methyl-D-aspartate (NMDA) receptor function is enhanced in HD at extrasynaptic sites, altering the balance of calcium-dependent neuronal survival versus death signalling pathways. Endoplasmic reticulum (ER) calcium handling is also abnormal in HD. The ER, which is continuous with the nuclear envelope, is purportedly involved in nuclear calcium signalling; based on this, we hypothesised that nuclear calcium signalling is altered in HD. We explored this hypothesis with calcium imaging techniques, including simultaneous epifluorescent imaging of cytosolic and nuclear calcium using jRCaMP1b and GCaMP3 sensors, respectively, in striatal spiny projection neurons in cortical-striatal co-cultures from the YAC128 mouse model of HD. Our data show contributions from a variety of calcium channels to nuclear calcium signalling. NMDA receptors (NMDARs) play an essential role in initiating action potential-dependent calcium signalling to the nucleus, and ryanodine receptors (RyR) contribute to both cytosolic and nuclear calcium signals. Unlike previous reports in glutamatergic hippocampal and cortical neurons, we found that in GABAergic striatal neurons, L-type voltage-gated calcium channels (CaV) contribute to cytosolic, but not nuclear calcium signalling. Calcium imaging also suggests impairments in nuclear calcium signalling in HD striatal neurons, where spontaneous action potential-dependent calcium transients in the nucleus were smaller in YAC128 striatal neurons compared to those of wild-type (WT). Our results elucidate mechanisms involved in action potential-dependent nuclear calcium signalling in GABAergic striatal neurons, and have revealed a clear deficit in this signalling in HD.
亨廷顿病（HD）是一种常染色体显性遗传的单基因疾病。在 HD 患者中，纹状体和皮层中的神经元退化，导致运动、精神和认知障碍。在许多神经退行性疾病中，包括 HD，突触功能和钙处理失调很常见。内质网（ER）钙处理在 HD 中也异常。内质网与核膜连续，据称参与核钙信号；基于此，我们假设 HD 中的核钙信号发生改变。我们使用钙成像技术探索了这一假设，包括使用 jRCaMP1b 和 GCaMP3 传感器分别对皮质纹状体共培养物中的纹状体棘突投射神经元进行胞质和核钙的共焦荧光成像。我们的数据表明，各种钙通道都对核钙信号有贡献。N-甲基-D-天冬氨酸（NMDA）受体（NMDAR）在启动动作电位依赖性钙信号向核的传递中起关键作用，而兰尼碱受体（RyR）对胞质和核钙信号均有贡献。与先前在谷氨酸能海马和皮质神经元中的报告不同，我们发现，在 GABA 能纹状体神经元中，L 型电压门控钙通道（CaV）有助于胞质钙信号，但不参与核钙信号。钙成像还表明，HD 纹状体神经元中的核钙信号受损，与野生型（WT）相比，YAC128 纹状体神经元中的核内自发性动作电位依赖性钙瞬变较小。我们的结果阐明了 GABA 能纹状体神经元中动作电位依赖性核钙信号转导所涉及的机制，并清楚地揭示了 HD 中这种信号转导的明显缺陷。
