Clinical Manifestations and Molecular Backgrounds of Parkinson's Disease Regarding Genes Identified From Familial and Population Studies

Abstract

Over the past 20 years, numerous robust analyses have identified over 20 genes related to familial Parkinson's disease (PD), thereby uncovering its molecular underpinnings and giving rise to more sophisticated approaches to investigate its pathogenesis. α-Synuclein is a major component of Lewy bodies (LBs) and behaves in a prion-like manner. The discovery of α-Synuclein enables an in-depth understanding of the pathology behind the generation of LBs and dopaminergic neuronal loss. Understanding the pathophysiological roles of genes identified from PD families is uncovering the molecular mechanisms, such as defects in dopamine biosynthesis and metabolism, excessive oxidative stress, dysfunction of mitochondrial maintenance, and abnormalities in the autophagy–lysosome pathway, involved in PD pathogenesis. This review summarizes the current knowledge on familial PD genes detected by both single-gene analyses obeying the Mendelian inheritance and meta-analyses of genome-wide association studies (GWAS) from genome libraries of PD. Studying the functional role of these genes might potentially elucidate the pathological mechanisms underlying familial PD and sporadic PD and stimulate future investigations to decipher the common pathways between the diseases.

Common genetic risk for Parkinson's disease and dysfunction of the endo-lysosomal system

“…Prior to this, PD was considered a prototypic non-genetic form of neurological disorder-occurring sporadically or spontaneously [28][29][30]. Since then, substantial advances have been made with regards to the identification of monogenic forms of Parkinson's disease, spanning autosomal dominant, autosomal recessive and X-linked patterns of inheritance [28][29][30]. The monogenic forms of PD may not always follow classical Mendelian inheritance, and may present with varying ages of disease onset, depending on the gene studied.…”

Genetics in Parkinson’s disease, state-of-the-art and future perspectives

“…Patients with four copies of the gene (triplicated locus) have younger age of onset and faster cognitive decline. 8 …”

“…This, in a self-sustained impaired cycle that affects protein clearance and cellular quality control, leads to the aggregation of misfolded proteins that accumulate in Lewy bodies—the pathological hallmark of PD. Misfolded proteins impair vesicles assembly and transport, lysosomal activity and chaperone-mediated autophagy, which altogether contribute to impair cellular dynamics, neuronal propagation of fibrils and Lewy bodies leading to neuronal death 8 ( Fig. 1 ).…”

“…This creates a vicious cycle, which leads to the accumulation of altered proteins impairing several pathways such as lysosomal-related autophagy and vesicle exocytosis. This contributes to the deposition of misfolded proteins and toxic compounds throughout the cell, leading to neuroinflammation that aggravates neuronal damage 7 , 8 , 17 , 21 ( Fig. 1 ).…”

The Role of Immune Dysfunction in Parkinson’s Disease Development

“…In a genetic mouse model using PARKIN knockout mice, neuroinflammation induced by active EAE leads to a robust activation of M1 microglia in the brains of knockout mice compared to wild-type controls [26]. It is worth noting that the autosomal recessive form of PD is characterized by the absence of Lewy bodies [77], suggesting that mitochondrial impairment can also trigger a microglial inflammatory response. Moreover, in the same genetic model, higher numbers of CD8 T-cells were detected in the brains of knockout mice compared to controls.…”