Microtubules: A Key to Understand and Correct Neuronal Defects in CDKL5 Deficiency Disorder?
Round 1
Reviewer 1 Report
In this manuscript, Barbiero et al. summarize recent findings of the interaction of CDKL5 with several microtubule-related proteins, discuss possible pathomechanisms through the loss-of-function of CDKL5, and suggest the microtubule-directed therapeutic strategy for CDKL5 deficiency disorders. The authors’ view is based on the up-to-date data from the wide range of literature, which does not seem biased. This article will help readers comprehend the cytoskeleton-related functions and loss-of-functionsof CDKL5.
I have only a few minor comments otherwise it is interesting and well-done piece of work.
Comments:
Line 29. Wasn’t the first cloning paper published in 1998? Lines 173, 196, 214, 233, 237, 253, 254, 263, 267, 269, 330, 385, 396.
Authors have used the term “Cdkl5”.
According to the “Guidelines for Nomenclature of Genes, Genetic Markers, Alleles, and Mutations in Mouse and Rat. Revised: August, 2018. International Committee on Standardized Genetic Nomenclature for Mice”
(http://www.informatics.jax.org/mgihome/nomen/gene.shtml), gene symbols are italicized, and begin with an uppercase letter, followed by all lowercase letters. Protein symbols use all uppercase letters, and are not italicized.
If “Cdkl5” is meant for the mouse protein, it should be “CDKL5”, if it is meant for the gene, “Cdkl5 (italic)”.
There are several grammatical and typographical errors, such as line 385 (has). Proofreadingof the English is necessary.
Author Response
We thank the reviewer for the comments that have all been considered in the revised version of the manuscript.
The paper describing the cloning of CDKL5 was indeed 1998. Moreover, Cdkl5 has been changed to CDKL5 and the manuscript has been checked for grammatical errors. All the changes are written in red.
Reviewer 2 Report
Barbiero et al.
Comments to authors:
This is a very well written and very focussed review that addresses the role of microtubules in CDKL5 disorder and the potential promise for targeting microtubules in CDKL5 disorder. The review is comprehensive and has a good discussion about the potential role of cdkl5 in regualting microtubules.
I only have a few comments that can be easily addressed:
1. "
The enlarged spine heads, which distinguish mushroom-shaped
257 spines, correlate with increased synaptic strength and various neurologic conditions characterised
258 by cognitive dysfunctions and autistic features have been linked to reduced number of mature
259 dendritic spines". - the autism phenotype in humans and mice can also result in an increase in the number of spines/excitatory synapses, not just a decrease.
2. It is clear that CDKL5 disorder is associated with a number of point mutations. The authors do not really discuss what the predicted or known effects of these are on microtubules and how this may impact pathology. This may be particularly interesting since CDKL5 disorder mutant forms of cdkl5 can be either hypomorphic or hypermorphic or null. Adding a paragraph on the predicted or known effects of these mutant forms and their relevance to the disorder would be beneficial
Author Response
We thank the reviewer for the nice comments that have all been considered in the revised version of the manuscript.
We have changed the sentence regarding dendritic spine defects in neurological diseases. Further, we have added section 5 describing the possible outcomes of different CDKL5 mutations. All the changes that we have made in the manuscript are indicated in red.
