Abstract
Parkinson's disease (PD) etiology is based upon interactions between genetic susceptibility and the environmental exposure. Multiple environmental factors inducing oxidative stress, mitochondrial damage, impairment of the neuroprotective and autophagic mechanisms are responsible for dopaminergic neurons death. Defining the contributions of genetic and environmental factors, may have important implications for understanding the pathogenesis of PD. The linkage analysis in Mendelian forms of PD especially in multiplex highly penetrant families is essential to elucidate biological mechanisms for PD susceptibility. Concerning the monogenic forms of PD were found mutations in 7 genes of AD transmission (SNCA, LRRK2, GIGYF2, VPS35, EIF4G1, HTRA2, TMEM230) and even more in those of AR transmission. This review aims to give an overview of the existing evidence of multiples molecular pathways involving cytoplasmic organelles’ function, neurodevelopmental mechanisms, synaptic vesicles endocytosis and trafficking, maintaining the integrity of the cytoskeleton and axonal transport in neurons. Understanding the molecular mechanisms following the identification of genes mutations and low-penetrance susceptibility alleles in familial and sporadic PD patients by genotyping technology and functional studies represent an essential step for the development of adequate biomarkers and potent therapies.
Highlights
Two neuropathological features were retained as crucial in Parkinson Disease (PD) pathogenesis, the dopaminergic neurons loss in the substantia nigra zona compacta [1] and the presence of eosinophilic intracytoplasmic inclusions mainly composed of α-synuclein [2]
The prevalence of familial forms of PD are between 6.4% and 21.6% of patient's relatives [3] but an exact diagnosis has proved elusive in PD relatives and the incidence of PD families in general population doesn't reflect the real frequency of the disease; the PD relatives are overrepresented and it must be considered the impact of environmental factors shared by the families members
The genome-wide association study found a deletion in tyrosine hydroxylase, enzyme involved in dopamine synthesis, in one adult PD [214] whereas missense mutations in tyrosine hydroxylase gene were already involved in infantile parkinsonism [215]
Summary
Two neuropathological features were retained as crucial in Parkinson Disease (PD) pathogenesis, the dopaminergic neurons loss in the substantia nigra zona compacta [1] and the presence of eosinophilic intracytoplasmic inclusions mainly composed of α-synuclein [2]. An Icelandic study raised the possibility that PD can have a familial component from a combination of environmental factors shared early in life and genetic factors [4]. The monozygotic twins have 100% concordance for the early-onset PD but the percentage is falling at 16.7% among the dizygotic twins related to the presence of environmental factors. The prevalence of familial forms of PD are between 6.4% and 21.6% of patient's relatives [3] but an exact diagnosis has proved elusive in PD relatives and the incidence of PD families in general population doesn't reflect the real frequency of the disease; the PD relatives are overrepresented and it must be considered the impact of environmental factors shared by the families members.
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