Molecular pathogenesis of Parkinson's disease: update

Abstract

Parkinson disease (PD) is a neurodegenerative disease characterised by progressive disturbances in motor, autonomic and psychiatric functions. Much has been learnt since the disease entity was established in 1817. Although there are well established treatments that can alleviate the symptoms of PD, a pressing need exists to improve our understanding of the pathogenesis to enable development of disease modifying treatments. Ten responsible genes for PD have been identified and recent progress in molecular research on the protein functions of the genes provides new insights into the pathogenesis of hereditary as well as sporadic PD. Also, genome wide association studies, a powerful approach to identify weak effects of common genetic variants in common diseases, have identified a number of new possible PD associated genes, including PD genes previously detected. However, there is still much to learn about the interactions of the gene products, and important insights may come from chemical and genetic screens. In this review, an overview is provided of the molecular pathogenesis and genetics of PD, focusing particularly on the functions of the PD related gene products with marked research progress.

The role of α-synuclein in neurodegeneration — An update

“…The most direct and compelling evidence for a functional role of AS in the pathogenesis of synucleinopathies is the causal relationship between genetic mutations and disease, and gene expression profiling of SN DA neurons gave further insight into PD pathology [193][194][195][196]. Approximately 7% of all PD cases result from a monogenic cause [35,197,198].…”

“…So far, 18 PARK loci have been described, and 10 genes have been linked to PD [35,196,198,[201][202][203][204][205][206] (Figure 3): Autosomaldominant (ad) parkinsonism is caused by the genes encoding AS or LRRK2 (leucine-rich repeat kinase 2, dardarin/PARK 8), clinically comparable to sporadic (s) PD [207][208][209], but with variable neuropathology [210,211], suggesting an upstream role of LRRK2 in protein aggregation [212]. Mutations in the LRRK2 gene, being the most common form of fPD in the world, cause impairment of protein degradation pathways, in particular autophagy, which can lead to accumulation of AS and unbiquitinated proteins, accumulation of oxidized proteins, inflammatory response, and increased apoptosis [213] (Figure 4).…”

“…DJ-1 (PARK7) or ATP13A2 (PARK9), and PARK2, which encodes E ubiquitin in the UPS [223] disrupting this ligase activity and mitochondrial function [224][225][226], lead to arPD, but also to sPD [198]. The characteristics and molecular biology of PARK1-18 and of other genes associated with PD have recently been summarized [196,204].…”

Proteolytic clearance of extracellular α-synuclein as a new therapeutic approach against Parkinson disease

“…Also characteristic is the presence of intracytoplasmic protein aggregates, Lewy bodies or Lewy neurites, as observed during other similar neurodegenerative diseases associated with aggregation-prone protein. 2 The intracytoplasmic protein aggregates observed in PD patients are mainly composed of α-syn, a small protein that is expressed abundantly in neuronal cells; it is localized mainly in the presynaptic nerve terminals. 3 Mutations of α-syn gene (A30P, E46K and A53T) and multiplications of the wild-type gene have been found to be associated with familial cases of early onset PD.…”

Transcriptome profiling of 6-OHDA model of Parkinson’s disease

“…Mutations in genes such as SNCA, PARK2, PINK1, PARK7 (DJ-1), and LRRK2 have been reported to lead to the development of monogenic forms of PD. Moreover, several candidate genes with an unclear role in the pathogenesis of PD have been identified [2,3]. However, the analysis of these genes does not allow the complete description of the contribution of genetic factors to the etiopathogenesis of the disorder.…”