Dr. Senckenbergisches Chronomedizinisches Institut, Goethe University, Frankfurt/Main, Germany.
Department of Neurology, University of Groningen, Groningen, The Netherlands.
Neuropathol Appl Neurobiol. 2016 Feb;42(2):153-66. doi: 10.1111/nan.12253. Epub 2015 Jul 2.
Polyglutamine (polyQ) diseases are characterized by the expansion of a polymorphic glutamine sequence in disease-specific proteins and exhibit aggregation of these proteins. This is combated by the cellular protein quality control (PQC) system, consisting of chaperone-mediated refolding as well as proteasomal and lysosomal degradation pathways. Our recent study in the polyQ disease spinocerebellar ataxia type 3 (SCA3) suggested a distinct pattern of protein aggregation and PQC dysregulation.
To corroborate these findings we have investigated immunohistochemically stained 5 μm sections from different brain areas of Huntington's disease (HD) and SCA3 patients.
Irrespective of disease and brain region, we observed peri- and intranuclear polyQ protein aggregates. A subset of neurones with intranuclear inclusions bodies exhibited signs of proteasomal dysfunction, up-regulation of HSPA1A and re-distribution of DNAJB1. The extent of the observed effects varied depending on brain area and disease protein.
Our results suggest a common sequence, in which formation of cytoplasmic and nuclear inclusions precede proteasomal impairment and induction of the cellular stress response. Clearly, impairment of the PQC is not the primary cause for inclusion formation, but rather a consequence that might contribute to neuronal dysfunction and death. Notably, the inclusion pathology is not directly correlated to the severity of the degeneration in different areas, implying that different populations of neurones respond to polyQ aggregation with varying efficacy and that protein aggregation outside the neuronal perikaryon (e.g. axonal aggregates) or other effects of polyQ aggregation, which are more difficult to visualize, may contribute to neurodegeneration.
多聚谷氨酰胺（polyQ）疾病的特征是疾病特异性蛋白中多态性谷氨酰胺序列的扩展，并表现出这些蛋白的聚集。这是由细胞蛋白质量控制（PQC）系统对抗的，该系统由伴侣介导的重折叠以及蛋白酶体和溶酶体降解途径组成。我们最近在多聚谷氨酰胺疾病脊髓小脑共济失调 3 型（SCA3）中的研究表明存在明显的蛋白聚集和 PQC 失调模式。
为了证实这些发现，我们用免疫组织化学方法对亨廷顿病（HD）和 SCA3 患者不同脑区的 5μm 切片进行了染色。
无论疾病和脑区如何，我们都观察到核周和核内聚谷氨酰胺蛋白聚集体。具有核内包涵体的神经元亚群表现出蛋白酶体功能障碍的迹象，HSPA1A 上调和 DNAJB1 重分布。观察到的效应的程度取决于脑区和疾病蛋白。
我们的结果表明存在一个共同的序列，其中细胞质和核内包涵体的形成先于蛋白酶体的损伤和细胞应激反应的诱导。显然，PQC 的损伤不是包涵体形成的主要原因，而是可能导致神经元功能障碍和死亡的后果。值得注意的是，包涵体病理学与不同区域变性的严重程度没有直接相关性，这意味着不同神经元群体对 polyQ 聚集的反应具有不同的效果，而神经元胞体外的蛋白聚集（例如轴突聚集）或其他更难可视化的 polyQ 聚集的影响可能导致神经退行性变。
