Another Small Step in the Battle Against Parkinson’s Disease

Neuropathological studies of the brain tissue from patients with Parkinson's disease (PD) reveal the presence of Lewy Bodies in dopaminergic neurons, although no one is sure whether these bodies are causal or a result of the disease process. Two individual proteins, a-synuclein and ubiquitin, are found to accumulate in the Lewy Body inclusions and, recently, research on these proteins has led to some interesting speculation about the causes of some rare familial forms of PD.

Missense mutations in the gene encoding the a-synuclein protein were found in families with an inherited autosomal dominant form of PD, and various mutations in the PARKIN gene were discovered in families with a rare autosomal recessive juvenile form of parkinsonism (AR-JP). A recent study by Shimura and colleagues has now provided a possible link between the mechanisms of disease for both types of familial PD. Knowing that parkin is a ubiquitin ligase, and speculating that parkin and a-synuclein might interact, they found that parkin regulates the degradation of an unusual form of a-synuclein through the attachment of ubiquitin. Ubiquitination of a protein by ubiquitin ligase usually targets that protein for destruction in the proteasome.

a-synuclein is a small phosphoprotein thought be to involved in synaptic vesicle transport. Normal a-synuclein has a tendency to form aggregates but neurons can get rid of these aggregates by labeling them with ubiquitin and targeting them for degradation, a system that apparently fails in patients with PD and AR-JP.

In contrast to the situation in patients with sporadic PD, the brains of AR-JP patients do not contain Lewy Bodies. Shimura et al. surmised that parkin might be required to catalyze the ubiquitination of a-synuclein; absence or impairment of parkin might lead to the accumulation of non-ubiquitinated a-synuclein. They found an interaction between a-synuclein and also found that the a-synuclein species interacting with parkin was glycosylated, giving it a larger molecular weight. The failure of mutant parkin to ubiquinate the glycoslyated a-synuclein means that neurons cannot degrade this form, leading to its accumulation in the brain. This suggests that the accumulation of glycosylated a-synuclein may be associated with the loss of neurons in AR-JP patients. To further support these studies it would be necessary to prove that other parkin substrates accumulate in the brains of these patients as well. Results of this kind have, in fact, just been provided by another study showing that another parkin substrate Pael-R (parkin-associated endothelin receptor-like receptor) does indeed accumulate in the brains of these patients. We'll await further research!


  1. Shimura H, Schlossmacher MG, Hattori N, Frosch MP, Trockenbacher A, Schneider R, et al. Ubiquitination of a new form of a-synuclein by parkin from human brain: Implications for Parkinson's disease. Science 2001;293:263-9.
  2. Imai Y, Soda M, Inoue H, Hattori N, Mizuno Y, Takahashi R. An unfolded putative transmembrane polypeptide, which can lead to endoplasmic reticulum stress, is a substrate of parkin. Cell 2001;105:891-902.