Besides the classic mutations in coding regions of genes, the critical role of gene expression regulators in disease states is increasingly recognized. The network of small non-coding microRNAs is crucial for the normal development and survival of distinct neuronal populations that are vulnerable in various neurodegenerative disorders. In midbrain dopaminergic neurons, which degenerate in Parkinson's disease (PD) causing motor signs and symptoms, disruption of this network results in their progressive loss associated with impaired motor activity in Drosophila and mouse models. Studies of families with dominantly inherited PD linked to multiplication of the α-synuclein gene locus indicate that the amount of this key pathogenic protein in neurons is an important determinant of its tendency to aggregate pathologically and increase neuronal susceptibility. Recent reports demonstrate that the α-synuclein mRNA is under negative control by at least two microRNAs, miR-7 and miR-153. In addition to studying the regulation of candidate genes by specific microRNA species, different profiling approaches are uncovering variations in the abundance of certain microRNAs that may prove to be relevant to the disease. For example, miR-133b is deficient in the PD midbrain as well as in mouse models, and miR-34b/34c are decreased in several affected brain regions in PD and incidental Lewy body disease. Polymorphisms in the 3'-untranslated region of microRNA target mRNAs, including in the gene encoding α-synuclein found in Genome Wide Association studies, are another potential reason for variations in the rate of protein production and thus disease risk. And finally, the impact of a disease associated gene product, and in particular LRRK2, on the microRNA network compounds the complexity of the interplay between the microRNA system and pathogenic proteins. The wealth of knowledge accumulating from these studies in a few short years holds considerable promise to harness its potential and translate it into therapeutic strategies for PD.
All Science Journal Classification (ASJC) codes
- Gene regulation
- MRNA translation