Parkinson’s disease (PD) is the most common neurodegenerative movement disorder in the world, affecting 1% of the population aged over sixty. The etiology and pathogenesis of PD remains elusive. Genetic contribution to the etiology of familial PD is well established. Causal mutations in the genes for alpha-synuclein (SNCA, PARK1), parkin (PRKN, PARK2), ubiquitin carboxy-terminal esterase L1 (UCHL1, PARK5), PTEN-induced putative kinase 1 (PINK1, PARK6), DJ-1 (PARK7), leucine-rich repeat kinase 2 (LRRK2, PARK8), ATPase type 13A2 (ATP13A2, PARK9), HtrA serine peptidase 2 (HTRA2, PARK13), phospholipase A2, group VI (PLA2G6, PARK14) and F-box only protein 7 (FBOXO7, PARK15) have been identified, indicating that dysregulation of protein processing pathway and impairment of mitochondrial function may contribute to the pathogenesis of PD. However, mutations in these genes do not explain the occurrence of disease in all patients. Other genetic variations, environmental factors as well as aging, are thought to contribute the development of the disease.
　　The pathological hallmarks of Parkinson’s disease (PD) are the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) as well as the presence of α-synuclein (α-syn) proteiniacous inclusions, known as Lewy bodies or Lewy neurites, in some of the remaining dopaminergic neurons. Two major features of α-syn, toxicity and transmission, which could help to understand the pathological characteristics of PD. The first feature of α-syn is that it confers cytotoxicity to recipient cells, especially when it is in an oligomeric state. This toxic form causes proteasome impairment, mitochondrial dysfunction, endoplasmic reticulum stress, oxidative stress, disruption of plasma membrane and pore formation which results in apoptosis pathway activation and consequent cell death. Another important feature is its ability to be transmitted from neuron to neuron through plasma membrane penetration, exosomes or endocytosis. The accumulation of Lewy bodies underwent an ascending pattern of progression, spreading from the lower brainstem and olfactory bulb into the limbic system and, eventually, to the neocortex, suggesting a propagation mechanism similar to prion diseases.
　　In this talk, I will focus on how these genes and prion-like theory play roles in the pathogenesis of PD. Understanding the complexity of α-syn oligomerization and formation of toxic species as well as the α-syn transmission could help us to identify successful therapeutic strategy to halt the disease.