Mutations in the small heat shock protein B8 gene (HSPB8/HSP22) have been associated with distal hereditary motor neuropathy, Charcot–Marie–Tooth disease, and recently distal myopathy. It is so far not clear how mutant HSPB8 induces the neuronal and muscular phenotypes and if a common pathogenesis lies behind these diseases. Growing evidence points towards a role of HSPB8 in chaperone-associated autophagy, which has been shown to be a determinant for the clearance of poly-glutamine aggregates in neurodegenerative diseases but also for the maintenance of skeletal muscle myofibrils. To test this hypothesis and better dissect the pathomechanism of mutant HSPB8, we generated a new transgenic mouse model leading to the expression of the mutant protein (knock-in lines) or the loss-of-function (functional knock-out lines) of the endogenous protein Hspb8. While the homozygous knock-in mice developed motor deficits associated with degeneration of peripheral nerves and severe muscle atrophy corroborating patient data, homozygous knock-out mice had locomotor performances equivalent to those of wild-type animals. The distal skeletal muscles of the post-symptomatic homozygous knock-in displayed Z-disk disorganisation, granulofilamentous material accumulation along with Hspb8, αB-crystallin (HSPB5/CRYAB), and desmin aggregates. The presence of the aggregates correlated with reduced markers of effective autophagy. The sciatic nerve of the homozygous knock-in mice was characterized by low autophagy potential in pre-symptomatic and Hspb8 aggregates in post-symptomatic animals. On the other hand, the sciatic nerve of the homozygous knock-out mice presented a normal morphology and their distal muscle displayed accumulation of abnormal mitochondria but intact myofiber and Z-line organisation. Our data, therefore, suggest that toxic gain-of-function of mutant Hspb8 aggregates is a major contributor to the peripheral neuropathy and the myopathy. In addition, mutant Hspb8 induces impairments in autophagy that may aggravate the phenotype.

小热激蛋白B8基因（HSPB8 / HSP22）与远端遗传性运动神经病，Charcot-Marie-Tooth病以及最近的远端肌病有关。到目前为止，尚不清楚突变体HSPB8如何诱导神经元和肌肉表型，以及这些疾病背后是否存在常见的发病机制。越来越多的证据表明，HSPB8在与伴侣相关的自噬中的作用已被证明是神经退行性疾病中清除聚谷氨酰胺聚集体的决定因素，而且也是维持骨骼肌肌原纤维的决定因素。为了验证这一假设并更好地剖析突变体HSPB8的致病机理，我们生成了一个新的转基因小鼠模型，导致该突变蛋白的表达（敲入系）或功能丧失（功能敲除系）的表达。内源蛋白Hspb8。纯合敲除小鼠出现运动神经缺陷，与周围神经退化和严重的肌肉萎缩有关，证实了患者的数据，而纯合敲除小鼠的运动能力与野生型动物相当。有症状的纯合敲入后的远端骨骼肌表现出Z盘紊乱，颗粒丝状物质的积聚以及Hspb8，αB-晶状蛋白（HSPB5 / CRYAB）和结蛋白的聚集。聚集体的存在与有效自噬标记减少有关。纯合敲入小鼠的坐骨神经的特征是症状发生前动物的症状发生前和Hspb8聚集体中的自噬能力较低。另一方面，纯合敲除小鼠的坐骨神经形态正常，其远端肌肉显示出异常的线粒体堆积，但肌纤维和Z线组织完整。因此，我们的数据表明，突变型Hspb8聚集体的毒性功能获得是周围神经病变和肌病的主要贡献者。此外，突变体Hspb8诱导自噬功能受损，可能加重表型。