The biochemistry of Parkinson's disease.
Several genes have been identified for monogenic disorders that variably resemble Parkinson's disease. Dominant mutations in the gene encoding alpha-synuclein enhance the propensity of this protein to aggregate. As a consequence, these patients have a widespread disease with protein inclusion bodies in several brain areas. In contrast, mutations in several recessive genes (parkin, DJ-1, and PINK1) produce neuronal cell loss but generally without protein aggregation pathology. Progress has been made in understanding some of the mechanisms of toxicity: Parkin is an E3 ubiquitin ligase and DJ-1 and PINK1 appear to protect against mitochondrial damage. However, we have not yet fully resolved how the recessive genes relate to alpha-synuclein, or whether they represent different ways to induce a similar phenotype.
Cookson
Mark R
MR
Cell Biology Section, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, Maryland 20892, USA. cookson@mail.nih.gov
D005808:Genes, Recessive; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008954:Models, Biological; D046912:Multiprotein Complexes; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics; D015513:Oncogene Proteins / Q000737:chemistry / Q000235:genetics; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry / Q000235:genetics; D000071617:Protein Deglycase DJ-1; D011494:Protein Kinases / Q000737:chemistry / Q000235:genetics; D051843:Synucleins; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000235:genetics; D051844:alpha-Synuclein; D000099202:PTEN-Induced Putative Kinase
D047908:Intracellular Signaling Peptides and Proteins; D046912:Multiprotein Complexes; D009419:Nerve Tissue Proteins; D015513:Oncogene Proteins; D046988:Proteasome Endopeptidase Complex; D000071617:Protein Deglycase DJ-1; D011494:Protein Kinases; D051843:Synucleins; D044767:Ubiquitin-Protein Ligases; D051844:alpha-Synuclein; D000099202:PTEN-Induced Putative Kinase; C497604:SNCA protein, human; C111567:parkin protein; C105131:PARK7 protein, human