. Distinct brain transcriptome profiles in C9orf72-associated and sporadic ALS. Nat Neurosci. 2015 Aug;18(8):1175-82. Epub 2015 Jul 20 PubMed.


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  1. I think this study provides an important resource for the field. The public availability of these types of data sets are essential to push the field forward and will be very valuable for testing new hypotheses—we will certainly be mining the data.

    It is interesting that the authors focused on brain areas that do not show significant degeneration in ALS. The advantage of this approach is that confounds associated with gross neuronal loss and gliosis are avoided. The big question is how well these changes reflect what is happening in degenerating neurons. It will also be interesting to determine which changes are due to RNA foci and which to dipeptide repeat protein toxicity.

  2. The most striking result of this complex transcriptome analysis was the specificity of C9ORF72-ALS cases to have alterations in the unfolded protein response pathway. It was reassuring to see that many of the genes with altered splicing were the same ALS-associated genes that are involved in RNA metabolism.

    I think this technique would be easily applicable to mouse research, which would allow for RNA analysis in the brain prior to death, making it easier to identify early pathways. Since the Petrucelli lab just published their C9 mouse model (Chew et al., 2015), it would not be difficult to apply these techniques to mice of varying stages of disease progression.


    . Neurodegeneration. C9ORF72 repeat expansions in mice cause TDP-43 pathology, neuronal loss, and behavioral deficits. Science. 2015 Jun 5;348(6239):1151-4. Epub 2015 May 14 PubMed.

    View all comments by Brian Freibaum
  3. This work establishes that dysregulation of splicing and polyadenylation occur significantly more frequently in C9ORF72 ALS than in sporadic ALS (SALS), with region-specific changes seen in the cerebellum and frontal cortex. Understanding both the similarities and differences between C9ORF72 ALS and SALS is essential for development of therapeutic strategies that target either or both groups of patients.

    It would be interesting to know how this aberrant RNA processing of the cerebellum compares to patients with C9ORF72 frontotemporal dementia, as well as whether this happens in the motor neurons and/or glial cells of the spinal cord. The dysregulation observed in the cerebellum and frontal cortex of C9ORF72 is also consistent with a recently published paper reporting aberrant RNA splicing in peripheral tissues of C9orf72-related ALS (Cooper-Knock et al., 2015). Thus, disruption of RNA processing is emerging as a major pathological mechanism in C9ORF72-ALS.


    . C9ORF72 GGGGCC Expanded Repeats Produce Splicing Dysregulation which Correlates with Disease Severity in Amyotrophic Lateral Sclerosis. PLoS One. 2015;10(5):e0127376. Epub 2015 May 27 PubMed.

    View all comments by Janine Kirby

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