|
Parkinson's Disease |
|
|
Parkinson's disease is characterized by the presence of Lewy bodies and the loss of dopamine-producing neurons in substantia nigra that controls muscle movement. The Lewy body is an abnormal structure found in certain areas of the brain. It contains a protein called a-synuclein, which plays the central role in Parkinson's disease and other diseases involving Lewy bodies, such as dementia with Lewy bodies, multiple system atrophy, and Hallervorden-Spatz disease (reference). a-Synuclein a-Synuclein is a 140 amino acid protein abundantly expressed in presynaptic terminals of vertebrates. One of its normal functions is to regulate dopamine transporter activities (reference). This protein contains an NAC region that is prone to aggregate, especially under oxidative stress (reference 1, reference 2, reference 3). The aggregated a-synuclein can inhibit the function of 26S proteasome (reference), which is important for the clearance of misfolded proteins and other target molecules. The dysfunction of proteasome will contribute to cell death. Two mutations, A53T and A30P, in a-synuclein have been identified in families with early-onset familial Parkinson's disease. These mutations may accelerate the aggregation of a-synuclein (reference). It is also interesting to note that, even without mutation, extra copies of the gene encoding a-synuclein can cause Parkinson's disease at an average age of just 34 (reference). a-Synuclein knockout mice are still viable and exhibit normal dopaminergic cell bodies and synapses (reference). In the absence of a-synuclein, mice are resistant to MPTP-induced toxicity (reference). MPTP is known to inhibit mitochondrial complex I, resulting in Parkinson-like symptoms. Another complex I inhibitor, rotenone, produces more widespread neurotoxicity when injected into rats (reference). Removing a-synuclein did not protect the rotenone-induced toxicity (reference). It is known that entry of MPTP into the dopamine neuron is mediated by dopamine transporter, whereas rotenone is highly lipophilic and may enter the neuron directly. Parkin Parkin is a 465 amino acid protein involved in the ubiquitin-proteasome system for the clearance of misfolded proteins and other target molecules. It serves as the E3 enzyme in the system. Mutations of the Parkin gene are associated with early onset Parkinson's disease (reference). Parkin does not seem to interact with native a-synuclein, but it does ubiquitinate an a-synuclein-interacting protein, synphilin-1 (reference). a-Synuclein, Parkin and synphilin-1 represent the major components of Lewy bodies. In the Lewy body, a-synuclein is also ubiquitinated (reference), possibly by Parkin. It seems that Parkin can protect the cell by specifically tagging modified (oxidized, aggregated, etc.) a-synuclein for destruction. Whether synphilin-1 plays a role in the recognition of modified a-synuclein remains to be investigated. DJ-1 Mutations in DJ-1 have been reported in families with early-onset Parkinson's disease (reference). The function of this protein is not clear. Its structure resembles a cysteine protease. Dimerization is required for its catalytic activity. The disease-associated L166P mutation may disrupt the dimerization (reference 1, reference 2). GSTO1 GSTO1 is involved in both Parkinson's disease and Alzheimer's disease (reference). The role of GSTO1 in these diseases is not clear. However, it is known that GSTO1 can modulate ryanodine receptors (reference), which are calcium channels in the endoplasmic reticulum of various cells, including neurons (reference). Ca2+ ions play an important role in neurotransmitter release. They also bind to a-synuclein to regulate its function. On the other hand, Ca2+ ions may exercise pathological effects by promoting oligomerization of a-synuclein (reference).
Review Articles: How does parkin ligate ubiquitin to Parkinson's disease - EMBO Reports, 2004. Parkin genetics: one model for Parkinson's disease - Human Molecular Genetics, 2004. a-Synuclein and Parkinson’s disease - FASEB J., 2004. Does a-synuclein modulate dopaminergic synaptic content and tone at the synapse? - FASEB J., 2004. Rare genetic mutations shed light on the pathogenesis of Parkinson disease - J. Clin. Invest., 2003. Structure/function of a-synuclein in health and disease - J. Neurochem., 2002.
|