Invertebrate Models Untangle the Mechanism of Neurodegeneration in Parkinson's Disease

Abstract

Parkinson's disease (PD) is the second most common neurodegenerative disease, afflicting ~10 million people worldwide. Although several genes linked to PD are currently identified, PD remains primarily an idiopathic disorder. Neuronal protein α-synuclein is a major player in disease progression of both genetic and idiopathic forms of PD. However, it cannot alone explain underlying pathological processes. Recent studies demonstrate that many other risk factors can accelerate or further worsen brain dysfunction in PD patients. Several PD models, including non-mammalian eukaryotic organisms, have been developed to identify and characterize these factors. This review discusses recent findings in three PD model organisms, i.e., yeast, Drosophila, and Caenorhabditis elegans, that opened new mechanisms and identified novel contributors to this disorder. These non-mammalian models share many conserved molecular pathways and cellular processes with humans. New players affecting PD pathogenesis include previously unknown genes/proteins, novel signaling pathways, and low molecular weight substances. These findings might respond to the urgent need to discover novel drug targets for PD treatment and new biomarkers for early diagnostics of this disease. Since the study of neurodegeneration using simple eukaryotic organisms brought a huge amount of information, we include only the most recent or the most important relevant data.

Keywords: DNA methylation; alpha-synuclein; epigenetic regulation; folate; neurodegeneration; protein aggregation; protein sorting; vesicular trafficking.

Figure 1

(A) Human α-synuclein gene contains six exons shown as vertical bars. The translation start codon ATG is located in exon 2. The sequence between two arrows contains a high density of CpG bases, which can be methylated (B,C). (B) Upper panel shows a small level of methylation (open circles) within the α-synuclein intron 1 region, allowing a high level of the gene expression (ON). Lower panel-methylation of cytosine residues (closed circles) downregulates expression of the α-synuclein gene. (C) DNA methylation catalyzed by methyltransferases (DNMTs) converts cytosine to 5-methylcytosine by transfer of methyl group from S-adenosylmethionine. This is one of several epigenetic mechanisms to control gene expression.