Ubiquitin-proteasome System Dysfunction Research Articles

Molecular pathways to neurodegeneration.

The molecular bases underlying the pathogenesis of neurodegenerative diseases are gradually being disclosed. One problem that investigators face is distinguishing primary from secondary events. Rare, inherited mutations causing familial forms of these disorders have provided important insights into the molecular networks implicated in disease pathogenesis. Increasing evidence indicates that accumulation of aberrant or misfolded proteins, protofibril formation, ubiquitin-proteasome system dysfunction, excitotoxic insult, oxidative and nitrosative stress, mitochondrial injury, synaptic failure, altered metal homeostasis and failure of axonal and dendritic transport represent unifying events in many slowly progressive neurodegenerative disorders.

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.