Kawahara Y, Mieda-Sato A.
TDP-43 promotes microRNA biogenesis as a component of the Drosha and Dicer complexes.
Proc Natl Acad Sci U S A. 2012 Feb 28;109(9):3347-52.
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This work of Yukio Kawahara and Ai Mieda-Sato is very interesting. It complements previous work from the groups of Don Cleveland, Bob Brown, and many others linking RNA metabolism to the pathology of TDP-43 in FTD and ALS. It also provides a strong clue that miRNAs may be involved in TDP-43 associated neurodegeneration, as also suggested by Francisco Baralle and myself (see Buratti et al., 2010 and Haramati et al., 2010).
The study here reveals facets of the molecular mechanism by which TDP-43 functions in regulation of miRNA biogenesis, both in the nucleus (with Drosha) and in the cytoplasm (with Dicer).
I like to think of several questions emerging from this work:
1. In what way do ALS-causing TDP-43 mutations impair TDP-43's interaction with Dicer or Drosha in vivo?
2. What part of TDP-43-associated pathology involves regulation of miRNA bioprocessing versus other events (including, e.g., splicing)?
3. What miRNAs are actually regulated by TDP-43 in relevant populations of authentic neurons (e.g., in the frontal cortex and motor neurons)?
4. What pathways do miRNA genes downstream of TDP-43 control?
All these make major challenges for follow-up work.
Buratti E, De Conti L, Stuani C, Romano M, Baralle M, Baralle F.
Nuclear factor TDP-43 can affect selected microRNA levels.
FEBS J. 2010 May;277(10):2268-81.
Haramati S, Chapnik E, Sztainberg Y, Eilam R, Zwang R, Gershoni N, McGlinn E, Heiser PW, Wills AM, Wirguin I, Rubin LL, Misawa H, Tabin CJ, Brown R, Chen A, Hornstein E.
miRNA malfunction causes spinal motor neuron disease.
Proc Natl Acad Sci U S A. 2010 Jul 20;107(29):13111-6.
The regulation of miRNA biogenesis by TAR DNA-binding protein 43 (TDP-43) represents a bridge between neurodegeneration and regulation of genes at the post-transcriptional level. TDP-43 is the major constituent of inclusions in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin positive inclusions (FTLD-TDP). Under physiological conditions, TDP-43 is localized in the nucleus of cells. This paper shows that TDP-43 can physically associate with the Drosha complex in the nucleus to alter expression of miRNAs in two cell lines, while knockdown of TDP-43 leads to reduction of at least six miRNAs. Under pathological conditions, TDP-43 is relocated to the cytoplasm and accumulates in inclusions. Since the paper also shows that TDP-43 can interact with the Dicer complex to promote production of a subset of miRNAs, accumulation of TDP-43 in inclusions during neurodegenerative disorders may prevent its functional role in miRNA biogenesis, leading to alteration of miRNA expression. For instance, TDP-43 depletion in Neuro2A cells led to a reduced level of miR-132 and attenuation of neurite outgrowth. This raises the possibility that TDP-43 inclusions as a secondary histopathological feature in other neurodegenerative disorders, such as Alzheimer’s disease, may also lead to alteration of miRNAs.
Based on our experience, a subset of miRNAs in late-onset Alzheimer’s disease is affected from early to late stages of disease. Is there an overlap of altered miRNAs in Alzheimer’s disease, ALS, and FTLD that can mechanistically define pathways and networks involved in aging and neuronal homeostasis?
There is now strong belief that we have the appropriate toolbox to study miRNAs and identify their targets, thus advancing our understanding of molecular mechanisms of neurodegeneration.