自噬-溶酶体途径在帕金森病相关神经变性疾病中的作用

The ubiquitin-proteasome system (UPS) and autophagy-lysosome pathway (ALP) are the two most important mechanisms that normally repair or remove abnormal proteins. Alterations in the function of these systems to degrade misfolded and aggregated proteins are being increasingly recognized as playing a pivotal role in the pathogenesis of many neurodegenerative disorders such as Parkinson's disease. Dysfunction of the UPS has been already strongly implicated in the pathogenesis of this disease and, more recently, growing interest has been shown in identifying the role of ALP in neurodegeneration. Mutations of alpha-synuclein and the increase of intracellular concentrations of non-mutant alpha-synuclein have been associated with Parkinson's disease phenotype. The demonstration that alpha-synuclein is degraded by both proteasome and autophagy indicates a possible linkage between the dysfunction of the UPS or ALP and the occurrence of this disorder. The fact that mutant alpha-synucleins inhibit ALP functioning by tightly binding to the receptor on the lysosomal membrane for autophagy pathway further supports the assumption that impairment of the ALP may be related to the development of Parkinson's disease.  In this review, we summarize the recent findings related to this topic and discuss the unique role of the ALP in this neurogenerative disorder and the putative therapeutic potential through ALP enhancement.

泛素-蛋白酶体系统(UPS)和自噬-溶酶体途径(ALP)是机体正常修复或者清除异常蛋白的最主要的两种机制。在帕金森病等诸多神经变性疾病中,这些系统降解错误折叠和聚集蛋白的功能改变所起的关键作用已逐渐被认识。UPS系统功能紊乱明显与这些疾病的病因相关，近来ALP在神经变性中的作用则越来越受到关注。Alpha-synuclein突变体和未突变alpha-synuclein的细胞内浓度增加与帕金森病表型有关。Alpha-synuclein既通过蛋白酶体又通过自噬降解的证据提示了UPS或者ALP功能紊乱和该疾病发病之间存在一个可能的联接。Alpha-synuclein突变体通过自噬途径与溶酶体膜上受体紧密结合从而抑制ALP功能的事实更进一步地支持此假设即：ALP受损可能与帕金森病的进展有关。在这篇综述中我们总结此主题新近的发现并且讨论ALP在神经变性疾病中的独特作用，从而推测通过提高ALP作为治疗方法的可能性。

Fig.1 Causes of protein aggregation and dopaminergic neurondeath.

Multiple factors, such as genetics, aging and environmental toxins, or combinations, have been implicated in the aetiology of Parkinson's disease. All these may directly or indirectly affect the function of protein degradation systems, including ubiquitin-proteasome system (UPS) and autophagy-lysosome pathway (ALP), and thereby, cause the death of dopamine neurons.

Fig. 2  Autophagy-lysosomepathway (ALP) in mammalian cells.

Generally, the cytosolic proteins and cell components are degraded through macroautophagy pathway. Inhibition of the autophagosome formationby 3-methyladenine (3-MA) without markedly affecting protein synthesis or ATP levels (Seglen and Gordon,1982), or inhibition of the fusion of autophagosome with lysosome by bafilomycin A1+(BafA1) through inhibiting vacuolar type H-ATPase (V-ATPase), may lead to the dysfunction of macroautophagy. In microautophagy, the lysosomal membrane itself deforms to engulf the cytosolic substrates. Specific cytosolic proteins that can be recognized by a cytosolic chaperone, the heat-shock cognate protein of 70 kDa (hsc70), which targets them to the surface of lysosomes, may be degraded through CMA pathway.

Fig. 3 Autophagy compensates for impaired UPS function.

Proteasome inhibition-induced dysfunction of UPS leads to neurodegeneration. When UPS is impaired, autophagy can be compensatively induced to help remove the excessive unwanted proteins causedby UPS dysfunction and rescues neurodegeneration. The activity of HDAC6, a microtubule-associated deacetylase that interacts with poly-ubiquitinated proteins, is essential for autophagy to compensate for impaired UPS function. HDAC6 rescues neurodegeneration associated with UPS dysfunctionin an autophagy-dependent manner (Pandeyetal., 2007).

Fig. 4  Signalling pathways in the regulation of autophagy.

Autophagy is activated in response to nutrient starvation, differentiation and
developmental triggers. It is an adaptive process responding to metabolic stresses that results in degradation of  intracellular proteins and organelles. There are three classes of phosphatidylinositol 3-kinase (PI3K) in mammalian cells. Class IPI3K is an inhibitor of autophagy. Stimulation of class IPI3K pathway through insulin receptor results in the activation of the mammalian target of rapamycin (mTOR), thereafter, inhibits autophagy. Phosphatase and tensinhomologue (PTEN) enhance the autophagy through the inhibition of class IPI3K. Class III PI3K is an activator of autophagy and plays a crucial role at an early step of autophagosome formation. The beclin1/PI3K-III complex is involved in the formation of autophagosomes and initiation of autophagy. Ambra1 (activatingmoleculeinbeclin1-regulated autophagy), is a positive regulator of  the beclin1-dependent programme of autophagy (Fimiaetal., 2007). Autophagy is regulated through energy metabolism. During the nutrient starvation or ATP deficiency due to mitochondrial complex I inhibition, autophagy is enhanced through the mTOR pathway. At the sequestration step, 3-MA interferes with the activity of class IIIPI3K to interrupt autophagy (Blommaartetal.,1997; Petiotetal., 2000). Wortmannin, LY294002 inhibit class III PI3K to reduce autophagy. Furthermore, neither wortmannin nor LY294002 displays selectivity for different members of the class IPI3K. At higher concentrations, wortmannin inhibits PI3K-related enzymes, such as mTOR. Rapamycin inhibits mTOR to induce autophagy. Mood-stabilizing drugs, such as lithium, carbamazepine and VPA, induce autophagy through inhibition of  inositolmonophosphatase (IMPase), which is mTOR-independent pathway.