The myosin VI interactome: the role of motor cargo/adaptor complexes and ubiquitin-binding during selective autophagy

我们的老龄化人口中，有相当大一部分人受到阿尔茨海默氏症、运动神经元或帕金森氏症等神经退行性疾病发病较晚的影响。更好地了解导致这些神经退行性疾病的原因可能会导致新的治疗和预防策略，或者至少可以改善受影响患者的生活质量。现在越来越多的研究表明，运动神经元疾病和某些形式的痴呆症与用于消化异常蛋白质或细胞缺陷部分的细胞通路中的缺陷有关。这些缺陷会导致这些蛋白质聚集成大团块，这可能会阻碍我们四肢神经中基本货物的运输，最终导致神经细胞死亡。我们的研究重点是特殊的分子马达蛋白质肌球蛋白VI，它沿着与所有其他马达相反的方向驱动货物到达细胞中的特定位置，就像火车沿着铁路网行驶到特定目的地一样。货物在我们研究中确定的特定适配器蛋白的帮助下连接到发动机上。新的结果表明，这种运动蛋白存在于死于阿尔茨海默病患者的神经细胞中的蛋白质块中。此外，最近有研究表明，将肌球蛋白VI与特定货物联系起来的视神经磷酸酶蛋白的错误(突变)会导致一种遗传性运动神经元疾病。因此，我们将探索肌球蛋白VI和视神经磷酸酶是否会移动和处置这些有毒的蛋白质块，并阻止它们的积聚，以避免神经细胞的死亡和随后的神经退行性疾病。因此，我们希望确定肌球蛋白VI及其接头蛋白在清除蛋白聚集体以保持神经细胞健康的重要途径中的确切作用。这将开辟新的研究领域，可能指导未来的临床研究以及潜在诊断工具和可能的治疗策略的开发。

A significant proportion of our ageing population is affected by the late onset of neurodegenerative disorders such as Alzheimer's, motor neuron or Parkinson's diseases. A better understanding of what causes these neurodegenerative diseases could lead to new therapeutic and preventive strategies or could at least improve the quality of life of the affected patients. More and more research now suggests that motor neuron disease and some forms of dementia are linked to defects in a cellular pathway that is used to digest abnormal proteins or defective parts of the cell. These defects can lead to an accumulation of these protein as large clumps, which may clog up the transport of essential cargo along nerves in our limbs and eventually cause the nerve cells to die. Our research is focused on the special molecular motor protein myosin VI, which drives cargo along tracks in the opposite direction to all other motors to specific sites in the cell, rather like a train running along a railway network to its specific destinations. The cargo is hooked up to the motor with the help of specific adaptor proteins that we have identified in our research. New results now show that this motor protein is present on protein lumps found in nerve cells from patients that died from Alzheimer's disease. Furthermore, it was recently shown that mistakes (mutations) in the protein optineurin, which links myosin VI to specific cargos, causes an inherited form of motor neuron disease. We will thus explore whether myosin VI and optineurin move and dispose of these toxic protein lumps and prevent their accumulation to avoid the death of nerve cells and subsequent neurodegenerative diseases.We thus hope to identify the precise roles of myosin VI and its adaptor proteins in the pathway that is important for clearance of protein aggregates to keep the nerve cells healthy. This will open up new areas of research that may guide future clinical studies and the development of potential diagnostic tools and possible therapeutic strategies.