Although the failure of the UPS has been implicated in both sporadic and familial forms of PD, it is unclear as to whether it is involved in the initiation or progression (or both) of the disease. It is hypothesized that mutations in parkin impair its normal ubiquitination activity, leading to an accumulation of proteins that overload the UPS and result in the selective death of neurons in the substantia nigra by a mechanism that is largely unknown. The paucity of Lewy bodies and therefore a lack of normal cellular defenses against excess levels of toxic proteins may manifest as early onset and severe neurodegeneration in parkin-associated PD. The pathogenic connection between the ubiquitination pathway and parkin-related PD has been established - the thrust should now be on understanding the mechanisms that cause and contribute to the development of disease.
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