Template:Expert-subject-multiple Template:PBB
Parkin is a protein which in humans is encoded by the PARK2 gene.[1][2] The precise function of this protein is unknown; however, the protein is a component of a multiprotein E3 ubiquitin ligase complex which in turn is part of the ubiquitin-proteasome system that mediates the targeting of proteins for degradation citation needed. Mutations in this gene are known to cause a familial form of Parkinson's disease known as autosomal recessive juvenile Parkinson disease.
How loss of function of the parkin protein leads to dopaminergic cell death in this disease is unclear. The prevailing hypothesis is that parkin helps degrade one or more proteins toxic to dopaminergic neurons. Putative substrates of parkin include synphilin-1, CDC-rel1, cyclin E, p38 tRNA synthase, Pael-R, synaptotagmin XI, sp22 and parkin itself (see also ubiquitin ligase). Additionally, Parkin contains a C-terminal motif that binds PDZ domains. Parkin has been shown to associate in a PDZ dependent manner with the PDZ domain containing proteins CASK and PICK1.
Parkinson's disease
PARK2 (OMIM *602544) is the parkin gene that may cause a form of autosomal recessive juvenile Parkinson disease (OMIM 600116) due to a mutation in the parkin protein. This form of genetic mutation may be one of the most common known genetic causes of early-onset Parkinson disease. In one study of patients with onset of Parkinson disease prior to age 40 (10% of all PD patients), 18% had parkin mutations, with 5% homozygous mutations.[3] Patients with an autosomal recessive family history of parkinsonism are much more likely to carry parkin mutations if age at onset is less than 20 (80% vs. 28% with onset over age 40).[4]
Patients with parkin mutations (PARK2) do not have Lewy bodies. Such patients develop a syndrome that closely resembles the sporadic form of PD; however, they tend to develop symptoms at a much younger age.
Interactions
Parkin (ligase) has been shown to interact with STUB1,[5] SEPT5,[6][7] Alpha-synuclein,[8][9] SNCAIP,[10] SYT11,[11] HSPA1A,[5] Multisynthetase complex auxiliary component p38,[12] CASK,[13] CUL1,[14] PDCD2,[15] HSPA8,[5] GPR37,[5][16] FBXW7[14] and Ubiquitin C.[9][17]
References
- ^ Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S, Yokochi M, Mizuno Y, Shimizu N (1998). "Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism". Nature. 392 (6676): 605–8. doi:10.1038/33416. PMID 9560156.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ Matsumine H, Yamamura Y, Hattori N, Kobayashi T, Kitada T, Yoritaka A, Mizuno Y (1998). "A microdeletion of D6S305 in a family of autosomal recessive juvenile parkinsonism (PARK2)". Genomics. 49 (1): 143–6. doi:10.1006/geno.1997.5196. PMID 9570960.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ Poorkaj P, Nutt JG, James D, Gancher S, Bird TD, Steinbart E, Schellenberg GD, Payami H (2004). "parkin mutation analysis in clinic patients with early-onset Parkinson [corrected] disease". Am. J. Med. Genet. A. 129 (1): 44–50. doi:10.1002/ajmg.a.30157. PMID 15266615.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Lohmann E, Periquet M, Bonifati V, Wood NW, De Michele G, Bonnet AM, Fraix V, Broussolle E, Horstink MW, Vidailhet M, Verpillat P, Gasser T, Nicholl D, Teive H, Raskin S, Rascol O, Destée A, Ruberg M, Gasparini F, Meco G, Agid Y, Durr A, Brice A (2003). "How much phenotypic variation can be attributed to parkin genotype?". Ann. Neurol. 54 (2): 176–85. doi:10.1002/ana.10613. PMID 12891670.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ a b c d Imai, Yuzuru (2002). "CHIP is associated with Parkin, a gene responsible for familial Parkinson's disease, and enhances its ubiquitin ligase activity". Mol. Cell. 10 (1). United States: 55–67. doi:10.1016/S1097-2765(02)00583-X. ISSN 1097-2765. PMID 12150907.
{{cite journal}}: Check date values in:|year=(help); Cite has empty unknown parameters:|laydate=,|laysummary=, and|laysource=(help); Unknown parameter|coauthors=ignored (|author=suggested) (help); Unknown parameter|month=ignored (help)CS1 maint: year (link) - ^ Choi, P (2003). "SEPT5_v2 is a parkin-binding protein". Brain Res. Mol. Brain Res. 117 (2). Netherlands: 179–89. doi:10.1016/S0169-328X(03)00318-8. ISSN 0169-328X. PMID 14559152.
{{cite journal}}: Check date values in:|year=(help); Cite has empty unknown parameters:|laydate=,|laysummary=, and|laysource=(help); Unknown parameter|coauthors=ignored (|author=suggested) (help); Unknown parameter|month=ignored (help)CS1 maint: year (link) - ^ Liu, Min (2008). "Parkin regulates Eg5 expression by Hsp70 ubiquitination-dependent inactivation of c-Jun NH2-terminal kinase". J. Biol. Chem. 283 (51). United States: 35783–8. doi:10.1074/jbc.M806860200. ISSN 0021-9258. PMID 18845538.
{{cite journal}}: Check date values in:|year=(help); Cite has empty unknown parameters:|laydate=,|laysummary=, and|laysource=(help); Unknown parameter|coauthors=ignored (|author=suggested) (help); Unknown parameter|month=ignored (help)CS1 maint: unflagged free DOI (link) CS1 maint: year (link) - ^ Choi, P (2001). "Co-association of parkin and alpha-synuclein". Neuroreport. 12 (13). England: 2839–43. ISSN 0959-4965. PMID 11588587.
{{cite journal}}: Check date values in:|year=(help); Cite has empty unknown parameters:|laydate=,|laysummary=, and|laysource=(help); Unknown parameter|coauthors=ignored (|author=suggested) (help); Unknown parameter|month=ignored (help)CS1 maint: year (link) - ^ a b Kawahara, Kohichi (2008). "alpha-Synuclein aggregates interfere with Parkin solubility and distribution: role in the pathogenesis of Parkinson disease". J. Biol. Chem. 283 (11). United States: 6979–87. doi:10.1074/jbc.M710418200. ISSN 0021-9258. PMID 18195004.
{{cite journal}}: Check date values in:|year=(help); Cite has empty unknown parameters:|laydate=,|laysummary=, and|laysource=(help); Unknown parameter|coauthors=ignored (|author=suggested) (help); Unknown parameter|month=ignored (help)CS1 maint: unflagged free DOI (link) CS1 maint: year (link) - ^ Chung, K K (2001). "Parkin ubiquitinates the alpha-synuclein-interacting protein, synphilin-1: implications for Lewy-body formation in Parkinson disease". Nat. Med. 7 (10). United States: 1144–50. doi:10.1038/nm1001-1144. ISSN 1078-8956. PMID 11590439.
{{cite journal}}: Check date values in:|year=(help); Cite has empty unknown parameters:|laydate=,|laysummary=, and|laysource=(help); Unknown parameter|coauthors=ignored (|author=suggested) (help); Unknown parameter|month=ignored (help); Unknown parameter|unused_data=ignored (help)CS1 maint: year (link) - ^ Huynh, Duong P (2003). "The autosomal recessive juvenile Parkinson disease gene product, parkin, interacts with and ubiquitinates synaptotagmin XI". Hum. Mol. Genet. 12 (20). England: 2587–97. doi:10.1093/hmg/ddg269. ISSN 0964-6906. PMID 12925569.
{{cite journal}}: Check date values in:|year=(help); Cite has empty unknown parameters:|laydate=,|laysummary=, and|laysource=(help); Unknown parameter|coauthors=ignored (|author=suggested) (help); Unknown parameter|month=ignored (help)CS1 maint: year (link) - ^ Corti, Olga (2003). "The p38 subunit of the aminoacyl-tRNA synthetase complex is a Parkin substrate: linking protein biosynthesis and neurodegeneration". Hum. Mol. Genet. 12 (12). England: 1427–37. doi:10.1093/hmg/ddg159. ISSN 0964-6906. PMID 12783850.
{{cite journal}}: Check date values in:|year=(help); Cite has empty unknown parameters:|laydate=,|laysummary=, and|laysource=(help); Unknown parameter|coauthors=ignored (|author=suggested) (help); Unknown parameter|month=ignored (help)CS1 maint: year (link) - ^ Fallon, Lara (2002). "Parkin and CASK/LIN-2 associate via a PDZ-mediated interaction and are co-localized in lipid rafts and postsynaptic densities in brain". J. Biol. Chem. 277 (1). United States: 486–91. doi:10.1074/jbc.M109806200. ISSN 0021-9258. PMID 11679592.
{{cite journal}}: Check date values in:|year=(help); Cite has empty unknown parameters:|laydate=,|laysummary=, and|laysource=(help); Unknown parameter|coauthors=ignored (|author=suggested) (help); Unknown parameter|month=ignored (help)CS1 maint: unflagged free DOI (link) CS1 maint: year (link) - ^ a b Staropoli, John F (2003). "Parkin is a component of an SCF-like ubiquitin ligase complex and protects postmitotic neurons from kainate excitotoxicity". Neuron. 37 (5). United States: 735–49. doi:10.1016/S0896-6273(03)00084-9. ISSN 0896-6273. PMID 12628165.
{{cite journal}}: Check date values in:|year=(help); Cite has empty unknown parameters:|laydate=,|laysummary=, and|laysource=(help); Unknown parameter|coauthors=ignored (|author=suggested) (help); Unknown parameter|month=ignored (help)CS1 maint: year (link) - ^ Fukae, Jiro (2009). "Programmed cell death-2 isoform1 is ubiquitinated by parkin and increased in the substantia nigra of patients with autosomal recessive Parkinson's disease". FEBS Lett. 583 (3). Netherlands: 521–5. doi:10.1016/j.febslet.2008.12.055. PMID 19146857.
{{cite journal}}: Check date values in:|year=(help); Cite has empty unknown parameters:|laydate=,|laysummary=, and|laysource=(help); Unknown parameter|coauthors=ignored (|author=suggested) (help); Unknown parameter|month=ignored (help)CS1 maint: year (link) - ^ Imai, Y (2001). "An unfolded putative transmembrane polypeptide, which can lead to endoplasmic reticulum stress, is a substrate of Parkin". Cell. 105 (7). United States: 891–902. doi:10.1016/S0092-8674(01)00407-X. ISSN 0092-8674. PMID 11439185.
{{cite journal}}: Check date values in:|year=(help); Cite has empty unknown parameters:|laydate=,|laysummary=, and|laysource=(help); Unknown parameter|coauthors=ignored (|author=suggested) (help); Unknown parameter|month=ignored (help)CS1 maint: year (link) - ^ Yu, Furong (2008). "Parkin is ubiquitinated by Nrdp1 and abrogates Nrdp1-induced oxidative stress". Neurosci. Lett. 440 (1). Ireland: 4–8. doi:10.1016/j.neulet.2008.05.052. ISSN 0304-3940. PMID 18541373.
{{cite journal}}: Check date values in:|year=(help); Cite has empty unknown parameters:|laydate=,|laysummary=, and|laysource=(help); Unknown parameter|coauthors=ignored (|author=suggested) (help); Unknown parameter|month=ignored (help)CS1 maint: year (link)
Further reading
External links
- GeneReviews/NCBI/NIH/UW entry on Parkin Type of Juvenile Parkinson Disease
- parkin+protein at the U.S. National Library of Medicine Medical Subject Headings (MeSH)