The Central Theme of Parkinson's Disease: alpha-Synuclein

Parkinson's disease (PD) is the second most common neurodegenerative disorder, defined by the presence of resting tremor, muscular rigidity, bradykinesia, and postural instability. PD is characterized by the progressive loss of dopaminergic neurons within the substantia nigra pars compacta of the midbrain. The neuropathological hallmark of the disease is the presence of intracytoplasmic inclusions, called Lewy bodies (LBs) and Lewy neurites (LNs), containing alpha-synuclein, a small protein which is widely expressed in the brain. The alpha-synuclein gene, SNCA, is located on chromosome 4q22.1; SNCA-linked PD shows an autosomal dominant inheritance pattern with a relatively early onset age, and it usually progresses rapidly. Three missense mutations, A53T, A30P, and E46K, in addition to gene multiplications of the SNCA have been described so far. Although it is clear that LBs and LNs contain mainly the alpha-synuclein protein, the mechanism(s) which leads alpha-synuclein to accumulate needs to be elucidated. The primary question in the molecular pathology of PD is how wild-type alpha-synuclein aggregates in PD, and which interacting partner(s) plays role(s) in the aggregation process. It is known that dopamine synthesis is a stressfull event, and alpha-synuclein expression somehow affects the dopamine synthesis. The aberrant interactions of alpha-synuclein with the proteins in the dopamine synthesis pathway may cause disturbances in cellular mechanisms. The normal physiological folding state of alpha-synuclein is also important for the understanding of pathological aggregates. Recent studies on the alpha-synuclein protein and genome-wide association studies of the alpha-synuclein gene show that PD has a strong genetic component, and both familial and idiopathic PD have a common denominator, alpha-synuclein, at the molecular level. It is clear that the disease process in Parkinson's disease, as in other neurodegenerative disorders, is very complicated; there can be several different molecular pathways which are responsible for diverse and possibly also unrelated functions inside the neuron, playing roles in PD pathogenesis.