Misfiring or misfolding – role of Kv3 potassium channels in central hearing loss and neurodegeneration

听力损失和神经退化是健康缺陷，开始逐渐，通常是多因素的起源。这使得很难确定原因，因此目前的医学集中在治疗症状，而不是治愈原因。尽管在这两个领域进行了数十年的研究，但缺乏在机械水平上将听力损失和神经退行性变联系起来的功能概念。这部分是因为在人口层面，直接和间接因素很难分开。在细胞水平上，中枢性听力损失可归因于听觉神经元中动作电位的时间精确度（计时）降低，而神经退行性疾病通常与病理性细胞内蛋白质聚集体的形成有关。更进一步，动作电位的时间可以归因于电压门控钾通道功能的变化，病理性蛋白质聚集体的形成与细胞内钙浓度增加有关。因此，本项目的主要目的是检验以下假设：听力损失和神经变性这两种疾病的共同细胞机制：由于动作电位持续时间延长导致的细胞内钙超载是毒性损伤的原因。人类脊髓小脑共济失调13型是一种常染色体显性遗传疾病，可导致小脑萎缩、运动协调受损和听力损失，表现为声音定位受损。所有这些都是由KCNC 3基因中的一个单点突变（R420 H）引起的，该基因编码电压门控钾通道的Kv3.3亚基。使用为该项目创建的新R420 H小鼠模型，我们将使用神经生理学来研究动作电位时程的变化如何影响钙离子流入神经元。动作电位延长会导致神经元放电率降低和时间精度降低。这将通过测量突触前和突触后活动在神经元回路水平进行评估。预期增加的细胞内钙浓度导致下游信号级联的过度刺激，这反过来增加了递质释放或导致蛋白质错误折叠和/或聚集作为神经变性的前体。我们将利用该项目的研究结果来确定听力损失和神经退行性变的常见细胞机制，建立大脑其他部位退行性变的早期听觉生物标志物，并启动未来的研究方向，调查Kv 3通道的自然年龄相关性下降如何可能成为R420 H模型以外的神经退行性疾病机制的基础。研究AP形状改变作为退行性过程的开始而不是相反的方面为我们理解神经元功能障碍和细胞死亡提供了一个概念上的转折点。

Hearing loss and neurodegeneration are health deficits that begin gradually and are usually multifactorial in origin. This makes it difficult to identify the causes, so that medicine currently concentrates on treating the symptoms rather than curing the causes. Despite decades of research in both fields, functional concepts that link hearing loss and neurodegeneration on a mechanistic level are lacking. This is partly because at the demographic level, direct and indirect factors are difficult to separate. At the cellular level, central hearing loss can be attributed to reduced temporal precision (timing) of action potentials in auditory neurons, while neurodegenerative diseases are usually associated with the formation of pathological intracellular protein aggregates. Taking this a step further, the timing of action potentials can be attributed to changes in the function of voltage-gated potassium channels and the formation of pathological protein aggregates is associated with increased intracellular calcium concentrations. Consequently, the primary aim of this project is to test the hypothesis that a common cellular mechanism underlies both diseases, hearing loss and neurodegeneration: intracellular calcium overload due to prolonged action potential duration as the cause of the toxic insult. Human spinocerebellar ataxia type13 is an autosomal dominant inherited disease that results in cerebellar atrophy, impaired motor coordination AND hearing loss in the form of impaired sound localization. All of this is caused by a single point mutation (R420H) in the KCNC3 gene, which codes for the Kv3.3 subunit of voltage-gated potassium channels. Using a new R420H mouse model created for this project, we will use neurophysiology to investigate how changes in action potential duration affect calcium influx into neurons. Prolonged action potentials should lead to reduced firing rates of the neurons and decreased temporal precision. This will be assessed at the neuronal circuit level by measuring pre- and postsynaptic activity. The expected increased intracellular calcium concentrations lead to overstimulation of downstream signaling cascades, which in turn increase transmitter release or cause protein misfolding and/or aggregation as precursors to neurodegeneration. We will use the findings of this project to identify common cellular mechanisms for hearing loss and neurodegeneration, to establish early auditory biomarkers for degeneration in other parts of the brain, and to initiate future research directions investigating how the natural age-related decline of Kv3 channels might underlie neurodegenerative disease mechanisms outside the R420H model. The aspect of investigating altered AP shapes as the beginning of a degenerative process rather than vice versa provides a conceptual turning point in our understanding of neuronal dysfunction and cell death.