Golgi stress response reprograms cysteine metabolism and confers cytoprotection in Huntington’s disease

Identification: Paul, Bindu



Golgi stress response reprograms cysteine metabolism and confers cytoprotection in Huntington's disease
Bindu D. Paul1, Juan I. Sbodio1, Solomon H. Snyder1
1Johns Hopkins University School of Medicine, Baltimore, MD, USA
*Corresponding Author
Equal contribution
Dysregulated cysteine metabolism is associated with several neurodegenerative disorders including Huntington's disease (HD). Understanding the fundamental mechanisms operating the metabolic signaling pathways pertaining to cysteine disposition in the brain during normal, healthy conditions is key to unravel how their breakdown occurs in pathological states such as HD, which is characterized by progressive neurodegeneration. To counter the challenges imposed by stressors, healthy cells are endowed with multiple stress response pathways. Golgi stress response comprises a set of distinct cellular stress signaling processes whose molecular components, although not yet precisely identified, have been implicated in several recently emerging studies. We show herein that Golgi stressors act via the Protein Kinase RNA-like ER Kinase/Activating Transcription Factor 4 (PERK/ATF4) signaling pathway. ATF4 is the master regulator of amino acid metabolism that is induced during amino acid depletion and cell stress. One of the genes regulated by ATF4 is cystathionine gamma lyase (CSE), a key enzyme in the reverse transsulfuration pathway, which plays central roles in the maintenance of amino acid homeostasis. CSE, the biosynthetic enzyme for cysteine and hydrogen sulfide, is depleted in HD, leading to impaired stress response. The depletion of CSE perturbs not only cysteine metabolism, but also that of other amino acids. Our studies identify for the first time, the elusive molecular link between the Golgi stress response and the reverse transsulfuration pathways. This pathway may be harnessed to ameliorate the toxicity associated with aberrant stress response in HD. The findings presented herein are relevant to a better understanding of the molecular changes occurring in the cells, during progressive neurodegeneration in HD as well as diseases involving imbalanced amino acid metabolism. Our results help pinpoint metabolic and signaling hubs for novel therapeutic intervention not only for HD but also for other neurodegenerative conditions.
1. Paul BD, Sbodio JI, Xu R, Vandiver MS, Cha JY, Snowman AM, Snyder SH. Nature 2014, 509:96-100.
2. Paul BD* and Snyder SH*. Trends Biochem Sci 2015, 40:687-700.
3. Sbodio JI#, Snyder SH* and Paul BD#*. Proc Natl Acad Sci USA 2016, 113:8843-8848.  
4. Sbodio JI#, Snyder SH* and Paul BD#*. Proc Natl Acad Sci USA 2017, In Press.
5. Paul BD* and Snyder SH*. Biochem Pharmacol 2017, In Press.
 #Co-first, *Co-corresponding
This work was supported by grants from USPHS (MH18501) to S.H.S. and the CHDI foundation to S.H.S. and B.D.P.



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