Peer review of: RNA-binding proteins Musashi and tau soluble aggregates initiate nuclear dysfunction (2020)

REVIEWERS' COMMENTS:
Reviewer #1 (Remarks to the Author):
Reviewer #2 (Remarks to the Author):
 This is a revised manuscript, and the authors have addressed satisfactorily to the concerns of this
 reviewer from the previous submission(s). Consequently, the manuscript is now significantly
 improved for publication.
 The authors have responded well to my comments. They have an interesting story examining the
 relationship between tau and MSI1,2 that represents a significant advance for the field. I
 understand that the COVID19 pandemic interfered with research, and find the manuscript to be
 much improved.
However, there is still one change that must be made. In lines 583-584, the authors state that "In
Tau KO mice, we did not observe big change in MSI1, while we observed a marked signal of MSI2
in cortex and hippocampus." The immunoblots demonstrate a significant age-related change in
MSI1 in Tau KO mice. This the authors must state somewhere that "Age causes a significant
increase in MSI1 (and change in the distribution of MSI2) in the brain." Otherwise the
interpretation is misleading.
So, in summary, a good study but please be rigorous in the interpretation! Ben Wolozin Reviewer #3 (Remarks to the Author):
In the work of Montalbano and co-workers an influence of pathogenic tau on the localization of
MSI1 and MSI2 in the AD, ALS and FRD in brains of human and mouse was carefully analysed.
They have explicitly demonstrated that pathogenic tau can interact/co-aggregate with MSI1 and
MSI2 and affects their localization. It can also disrupt the nucleocytoplasmic transport and as such
affect the nuclear proteins localization and functionality as well as chromatin remodelling.
Therefore, I think that a new title of the manuscript (“RNA-Binding Proteins Musashi and Tau
soluble aggregates initiate nuclear dysfunction”) reflects better its content and conclusions.
The authors have also significantly improved their manuscript and have provided convincing
answers to the reviewers. Their results are novel and would significantly contribute into
understanding of the pathogenic tau and MSI1 and MSI2 role in the neurodegenerative diseases,
such as Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS) and Frontotemporal
dementia (FTD).
 Therefore, I would strongly recommend this manuscript for the publication in Nature
 Communication.
 Minor:
 I would suggest a few minor changes:
 Page 31:
 In the added paragraph on this page I would recommend to give a reference in the sentence: “On
 the other hand, toxic tau is also compromising RanGTP/RanGDP gradient that would also result in
 the reduced amount of the NLS-cargo in the cell nuclei (Eftekharzadeh et. al, 2018).”
 I would also propose to rewrite the sentence in page 31 as follows:
 “Nup50 or Nup153, which both have NLS-like-sequences and can also interact with nuclear
 transport receptors, are also reduced in the nuclear fraction and significantly elevated in the
 cytoplasm that might indicate that their recruitment during NPCs assembly is hindered in the
 presence of the pathogenic tau.”
I think this would be more appropriate.