Paper Tools Add to my Library Share How would you like to share? Facebook Twitter LinkedIn Back to the Top Alzforum Recommends
University of Kentucky
Jongpil Kim and colleagues from Asa Abeliovich's group have produced a very important work that indicates a particular microRNA (miRNA) may play a critical role in Parkinson disease. This study is important for a number of reasons. First, it indicates a discrete role for a particular miRNA in dopaminergic function; second, previously no particular miRNA-mRNA pair had been strongly implicated in a prevalent neurodegenerative disease. In other words, these investigators have provided plausible molecular neurobiological breakthroughs for both miRNA function and dysfunction.
The authors use various means to indicate that a particular miRNA—miR-133b—is relatively highly expressed at the tissue level in midbrain under normal conditions, but not during Parkinson disease. The main point they demonstrate conclusively is that knocking out miRNAs generally in vivo, or miR-133b by itself in culture, dramatically decreases tyrosine hydroxylase and dopamine transporter (DAT) levels in dopaminergic neurons. (The paper includes some gorgeous, albeit digitally rendered photomicrographs.) The data also support the hypothesis that miR-133b and the paired-like homeodomain transcription factor PITX3 regulate each other's expression.
The data is very persuasive. At the same time, several points may merit reflection.
miR-133 was previously described in a number of studies in connection with skeletal and cardiac muscle. miR-133a differs from miR-133b only at the 3' end by a single nucleotide (G for miR-133a, A for miR-133b). Theoretically this should alter the biological “activity” very little (although work from Joshua Mendell's lab at Johns Hopkins showed that the 3' end of miR-29 has an important role in trafficking the miRNA to either cytoplasm or cell nucleus). It remains to be seen whether miR-133b is indeed “specific”
to midbrain neurons, and this brings up one of the few weaknesses of this study: I would have liked to see in-situ hybridization localizing this miRNA in human tissue. After all, substantia nigra neurons represent a small minority of “midbrain” cells. Also, while the authors do show the relative amount of miR-133a and miR-133b in the brains, there is no indication of the absolute amount expressed, which is also important. If miR-133a is still present in more abundant quantities than miR-133b, why would things alter much inside the cells when miR-133b decreased?
Another issue with regard to this paper is that Parkinson disease is now considered a “synucleinopathy” as much as it is a “dopamine neuronopathy.” Cerebral cortical and brainstem diseases such as dementia with Lewy bodies and multiple system atrophy are in some ways more closely tied by pathoetiology to Parkinson's than, for example, MPTP toxicity, which only affects substantia nigra dopaminergic neurons. Hence, the focus of research has been more on protein degradation/ubiquitination, oxidation, folding, and so forth, rather than on the particular pathways involved with dopaminergic function. However, this paper demonstrates perhaps a new component of a “downward” spiral during the disease.
These considerations aside, this paper represents a true landmark in tying a particular miRNA to neurodegeneration. I look forward with great anticipation to follow-up studies in this explosive field.