Parkin- and PINK1-Dependent Mitophagy in Neurons: Will the Real Pathway Please Stand Up?
Parkin- and PINK1-Dependent Mitophagy in Neurons: Will the Real Pathway Please Stand Up?
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DOI：
10.3389/fneur.2013.00100
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发表时间：
2013
影响因子：
3.4
通讯作者：
Fon EA
中科院分区：
文献类型：
--
作者：
Grenier K;McLelland GL;Fon EA
帕金森病（PD）的特征是黑质多巴胺能神经元的大量变性。虽然大多数PD病例是散发性的，但约5-10%的病例是家族性的，并与遗传因素有关。parkin或PINK 1这两个因子的丢失导致PD的早期发作形式。重要的是，最近的研究表明，parkin在影响线粒体稳态的共同遗传途径中在PINK 1下游发挥作用。更确切地说，parkin已被证明以PINK 1依赖性方式介导受损线粒体的自噬（线粒体自噬）。然而，大部分表征该途径的工作已经在过表达高水平parkin的永生化细胞系中进行。相比之下，内源性parkin和PINK 1是否或如何促进神经元中的线粒体自噬尚不清楚。在这里，我们回顾了最近的工作，解决parkin/PINK 1依赖的线粒体自噬在神经元中的作用。显然，线粒体自噬途径在神经元和永生化细胞中在空间和动力学上有所不同，因此可能在其最终结果和功能上有所不同。虽然有证据表明parkin可以易位到神经元中的线粒体，但神经元中parkin募集下游的线粒体自噬的功能和机制仍有待澄清。此外，值得注意的是，大多数工作都集中在parkin/PINK 1线粒体自噬的下游信号传导事件，而上游信号传导途径仍然比较差的特点。确定触发parkin/PINK 1线粒体自噬的上游信号机制将有助于解释影响PD线粒体功能的损伤的性质，更好地理解神经元中的这些通路将是确定PD新治疗靶点的关键。
Parkinson’s disease (PD) is characterized by massive degeneration of dopaminergic neurons in the substantia nigra. Whereas the majority of PD cases are sporadic, about 5–10% of cases are familial and associated with genetic factors. The loss of parkin or PINK1, two such factors, leads to an early onset form of PD. Importantly, recent studies have shown that parkin functions downstream of PINK1 in a common genetic pathway affecting mitochondrial homeostasis. More precisely, parkin has been shown to mediate the autophagy of damaged mitochondria (mitophagy) in a PINK1-dependent manner. However, much of the work characterizing this pathway has been carried out in immortalized cell lines overexpressing high levels of parkin. In contrast, whether or how endogenous parkin and PINK1 contribute to mitophagy in neurons is much less clear. Here we review recent work addressing the role of parkin/PINK1-dependent mitophagy in neurons. Clearly, it appears that mitophagy pathways differ spatially and kinetically in neurons and immortalized cells, and therefore might diverge in their ultimate outcome and function. While evidence suggests that parkin can translocate to mitochondria in neurons, the function and mechanism of mitophagy downstream of parkin recruitment in neurons remains to be clarified. Moreover, it is noteworthy that most work has focused on the downstream signaling events in parkin/PINK1 mitophagy, whereas the upstream signaling pathways remain comparatively poorly characterized. Identifying the upstream signaling mechanisms that trigger parkin/PINK1 mitophagy will help to explain the nature of the insults affecting mitochondrial function in PD, and a better understanding of these pathways in neurons will be the key in identifying new therapeutic targets in PD.
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影响因子：
3.5
作者：
Chan NC;Salazar AM;Pham AH;Sweredoski MJ;Kolawa NJ;Graham RL;Hess S;Chan DC
通讯作者：
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影响因子：
3.5
作者：
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DOI：
10.1073/pnas.261560998
发表时间：
2001-12-18
影响因子：
11.1
作者：
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通讯作者：
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影响因子：
4.8
作者：
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