Molecular mechanisms of neurodegeneration in Parkinson's disease: clues from Mendelian syndromes.
The recent identification and characterization of gene products responsible for familial forms of Parkinson disease (PD) have provided significant insights into the pathogenesis of PD. Collectively, these studies point towards ubiquitin-proteasome system (UPS) dysfunction as an underlying mechanism responsible for dopaminergic cell death in PD. Emerging evidence further indicates a complex interplay between UPS derangements and other PD pathogenetic factors, all interwoven in an integrated network leading to dopaminergic cell death in PD. Taken together, these findings suggest that neuronal degeneration in PD is a result of a cascade of events, rather than a primary pathogenic event. Here, we review the clues uncovered from various Mendelian-inherited forms of PD that have helped shaped our understanding of the molecular mechanisms underlying PD pathogenesis.
Lim
Kah Leong
KL
Neurodegeneration Research Laboratory, National Neuroscience Institute, 11 Jalan Tan Tock Seng, Singapore 308433. Kah_Leong_Lim@ttsh.com.sg
Lim
Tit Meng
TM
D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008959:Models, Neurological; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism; D009410:Nerve Degeneration / Q000235:genetics* / Q000503:physiopathology*; D009419:Nerve Tissue Proteins / Q000235:genetics; D010300:Parkinson Disease / Q000235:genetics* / Q000503:physiopathology*; D046988:Proteasome Endopeptidase Complex; D051843:Synucleins; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics
D009097:Multienzyme Complexes; D009419:Nerve Tissue Proteins; D051843:Synucleins; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex