Nature:自噬作用與泛素—蛋白酶體系統之間的關係

    生物谷報導：對於一個細胞來說，要除去隨著時間推移所積累的不合適的蛋白主要有兩個通道：泛素—蛋白酶體系統和自噬作用，後者指的是通過一個細胞自身的溶酶體細胞器來使該細胞自己的組成部分自我破壞。用泛素—蛋白酶體系統已被瓦解了的一種神經退化疾病的果蠅模型所作的研究表明，自噬作用可以補償這種損失。兩個蛋白破壞通道在體內是聯繫在一起的，與微管相關的組蛋白去乙醯化酶HDAC6充當二者之間的聯繫。HDAC6的表達足以誘發自噬作用，使果蠅的神經退化得以挽救。這些發現反映了自噬作用與泛素—蛋白酶體系統之間的關係，並且對於了解與蛋白有關的神經退化疾病的發病機理及可能的治療方法也有參考意義。（引自 Nature asia）

 

原始出處:

Nature 447, 860-864 (14 June 2007) | doi:10.1038/nature05853; Received 19 December 2006; Accepted 16 April 2007

HDAC6 rescues neurodegeneration and provides an essential link between autophagy and the UPS

Udai Bhan Pandey1, Zhiping Nie1, Yakup Batlevi2, Brett A. McCray1, Gillian P. Ritson1, Natalia B. Nedelsky1, Stephanie L. Schwartz1, Nicholas A. DiProspero3, Melanie A. Knight3, Oren Schuldiner4, Ranjani Padmanabhan5, Marc Hild5, Deborah L. Berry2, Dan Garza5, Charlotte C. Hubbert6, Tso-Pang Yao6, Eric H. Baehrecke2 & J. Paul Taylor1

1. Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
2. Center for Biosystems Research, University of Maryland Biotechnology Institute, College Park, Maryland 20742, USA
3. Neurogenetics Branch, NINDS, NIH, Bethesda, Maryland 20817, USA
4. Department of Biological Sciences, Stanford University, Stanford, California 94305, USA
5. Novartis Institutes for Biomedical Research, Cambridge, Massachusetts 02139, USA
6. Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina 27710, USA

Correspondence to: J. Paul Taylor1 Correspondence and requests for materials should be addressed to J.P.T. (Email: [e-mail]).

A prominent feature of late-onset neurodegenerative diseases is accumulation of misfolded protein in vulnerable neurons1. When levels of misfolded protein overwhelm degradative pathways, the result is cellular toxicity and neurodegeneration2. Cellular mechanisms for degrading misfolded protein include the ubiquitin-proteasome system (UPS), the main non-lysosomal degradative pathway for ubiquitinated proteins, and autophagy, a lysosome-mediated degradative pathway3. The UPS and autophagy have long been viewed as complementary degradation systems with no point of intersection4, 5. This view has been challenged by two observations suggesting an apparent interaction: impairment of the UPS induces autophagy in vitro, and conditional knockout of autophagy in the mouse brain leads to neurodegeneration with ubiquitin-positive pathology6, 7, 8, 9. It is not known whether autophagy is strictly a parallel degradation system, or whether it is a compensatory degradation system when the UPS is impaired; furthermore, if there is a compensatory interaction between these systems, the molecular link is not known. Here we show that autophagy acts as a compensatory degradation system when the UPS is impaired in Drosophila melanogaster, and that histone deacetylase 6 (HDAC6), a microtubule-associated deacetylase that interacts with polyubiquitinated proteins10, is an essential mechanistic link in this compensatory interaction. We found that compensatory autophagy was induced in response to mutations affecting the proteasome and in response to UPS impairment in a fly model of the neurodegenerative disease spinobulbar muscular atrophy. Autophagy compensated for impaired UPS function in an HDAC6-dependent manner. Furthermore, expression of HDAC6 was sufficient to rescue degeneration associated with UPS dysfunction in vivo in an autophagy-dependent manner. This study suggests that impairment of autophagy (for example, associated with ageing or genetic variation) might predispose to neurodegeneration. Morover, these findings suggest that it may be possible to intervene in neurodegeneration by augmenting HDAC6 to enhance autophagy.

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