The case for therapeutic proteostasis modulators.
A functional ubiquitin proteasome pathway (UPP) is vital for all eukaryotic cellular systems and therefore any alteration in this critical component of proteostasis machinery has rpotential pathological consequences. A proteostasis imbalance can be induced by environmental pollutants, age or genetic factors. Though the exact underlying mechanisms are unclear, a decrease in proteasome activity weakens the homeostatic cellular capacity to remove proteins that are either misfolded or need to be replenished, which favors the development of neurodegenerative, cardiac and other conformational diseases. In contrast, induction of proteasome activity is an attribute of many diseases including muscle wasting, sepsis, cachexia and uraemia. In the case of misfolded protein disorders, higher degradation of a single protein leads to the pathophysiological consequences due to the absence of functional protein. Therefore, selective proteostasis inhibition is a potential treatment strategy for misfolded protein disorders, while broad-spectrum proteasome inhibitor drugs are designed to target tumor metastasis. In contrast, for muscle wasting and neurodegeneration, the use of proteostasis-activating or modulating compounds could be more effective.
Neeraj
N
Vij
D002908:Chronic Disease; D016503:Drug Delivery Systems; D006706:Homeostasis; D006801:Humans; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects* / Q000378:metabolism; D017510:Protein Folding; D011506:Proteins / Q000378:metabolism*; D014452:Ubiquitins / Q000378:metabolism
D011506:Proteins; D014452:Ubiquitins; D046988:Proteasome Endopeptidase Complex
Oncologist. 2003;8(6):508-13
14657528
Clin Cancer Res. 2004 Jun 15;10(12 Pt 1):3954-64
15217925
Thromb Haemost. 2006 Jan;95(1):166-73
16543976
Nephrol Dial Transplant. 2001;16 Suppl 1:60-2
11369823
FASEB J. 2004 Feb;18(2):272-9
14769821
Ann Rheum Dis. 2006 Nov;65 Suppl 3:iii37-40
17038470
Mol Cancer Ther. 2006 Dec;5(12):3052-61
17172407
Free Radic Biol Med. 2006 Mar 15;40(6):1034-44
16540399
Rev Neurosci. 2006;17(3):309-57
16878402
Neurosci Lett. 2006 May 8;398(3):300-5
16490315
Blood. 2007 Mar 1;109(5):2100-5
17095627
FEBS Lett. 2006 Jul 10;580(16):3989-94
16806194
Annu Rev Biochem. 2005;74:739-89
15952902
Br J Clin Pharmacol. 2002 Sep;54(3):269-76
12236847
Clin Chem. 2006 Nov;52(11):2079-86
16990418
Cell. 2010 Aug 20;142(4):613-24
20723761
Physiol Rev. 2006 Oct;86(4):1133-49
17015486
J Biol Chem. 2010 Aug 27;285(35):27385-27395
20605781
N Engl J Med. 2003 Jun 26;348(26):2597-8
12826633
Neurotox Res. 2004;6(6):463-8
15658001
Free Radic Biol Med. 2006 Jun 15;40(12):2232-41
16785037
J Biol Chem. 2003 Jun 13;278(24):21517-25
12676932
Mutat Res. 2005 Jan 6;569(1-2):29-63
15603751
J Clin Invest. 2005 Feb;115(2):268-81
15690081
J Neuropathol Exp Neurol. 2004 May;63(5):484-98
15198127
Proc Natl Acad Sci U S A. 2004 Jun 15;101(24):8894-9
15178764
BMC Biochem. 2007 Nov 22;8 Suppl 1:S3
18047740