The manuscript by E Thornburg-Suresh and DW Summers is an excellent and comprehensive review on the role of Stathmin proteins and in particular Stathmin 2 in axonal maintenance and neuronal function. The review is timely given recent advances in the understanding of Stmn2 misexpression and dysfunction in amyotrophic lateral sclerosis (ALS), other motor neuron diseases as well as frontotemporal dementia (FTD). These findings are of potential therapeutic relevance underscoring the scope of the review.
In general, the manuscript is well structured and clearly written. There are however some floppy terms and phrases which should be corrected, see minor points. More importantly three conceptual aspects need to be thoroughly adressed as detailed in the major points.

Major points :
1. The ms repeatedly states that Stmn2 expression is reduced in ALS (e.g. abstract line 40 ''Stmn2 is depleted in Amyotrophic Lateral Sclerosis'', main text line 315 ''Stmn2 is depleted in ALS patients''. This is only partially correct and thus overstatement. Indeed, Stmn2 levels are reduced in the most frequent forms of sporadic and familial ALS. The notable exception are rare, mutant SOD-associated forms of ALS where Stathmin 2 levels are increased rather than reduced. This difference is important since it stems from a major biological difference between these types of ALS. Indeed, TDP-43 cytoplasmic mislocalization is a hallmark of ALS associated with mutations in TDP-43 (as the authors correctly state) and also with ALS associated with mutations in other major ALS genes such as C9orf72. Yet, TDP-43 mislocalization and hence Stmn2 missplicing and downregulation are not associated with mutant SOD1-linked ALS. This provides the most likely explanation for the findings of Bellouze et al in their paper on mutant SOD1G85R or SOD1G93A expressing motor neurons and mice (reference 108). The functionally different mechanisms of Stathmin regulation in TDP-43 associated and mutant SOD-associated forms of ALS should be clearly stated and discussed.

1. The authors should include several interesting studies from the Haase and Sendner labs. Martin et al first showed that pmn mice with progressive motor neuronopathy carry a point mutation in the last codon of the tubulin chaperone Tbce (Martin et al. (2002) which destabilizes the TBCE protein, thereby leading to reduced axonal tubulin routing and progessive axonal microtubule loss (Schäfer et al. 2007). Bellouze et al. (2014) showed that TBCE destabilization in pmn mice causes disrupts an ARF1/TBCE cross-talk perturbing COPI vesicle formation and tubulin polymerization which are essential for Golgi maintenance. Later on, Yadav et al. (2016) demonstrated that accumulating neurofilaments associate with stathmin-1 in mutant pmn motoneurons. Depletion of neurofilaments by genetic knockout of the neurofilament light chain gene Nefl increased interaction of Stmn1 with the signaling molecule Stat3 and stabilized microtubules in pmn motoneurons.
   Taken together, these studies provide an important functional link between tubulin folding and polymerization, Stathmin regulation and axonal maintenance.
2. Two additional figures should be provided to illustrate main points in a comprehensive way to the non-specialist reader. First, a figure depicting the domain organization of the four Stathmin proteins Stmn1 to Stmn4. Second a figure showing the detailed mechanism of Stmn2 missplicing due to pathological nuclear TDP-43 depletion, cytoplasmic TDP-43 accumulation and TDP-43 aggregation. The figure should illustrate that Stmn2 mRNA posseses several TDP-43 binding sites which are crucial for normal Stmn2 mRNA splicing and exon inclusion. Pathological nuclear TDP-43 depletion leads to Stmn2 missplicing which in turn causes premature polyadenylation and synthesis of a small, C-terminally truncated Stmn2 protein. These aspects which are at the heart of the review should also be presented in detail in the main text.

Minor points
Line 40. Stmn2 is depleted in Amyotrophic Lateral Sclerosis
34 microtubule-associated
56 is also contribute -> contributes
62 neuronal cell body
66. degeneration of axons ... debilitating event in many neurodegenerative diseases. rephrase debilitating to critical, damaging or else
68 protein, vesicle and organelle transport
83 intertwined with amyotrophic lateral sclerosis (ALS) pathology rephrase most forms of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia
96 in the Stathmin family
102 Stathmin family expression -> Expression of stathmins
105 Stmn2-4 -> Stathmins 2 to 4 or Stmn2, Stmn3 and Stmn4, see also 137 Stmns1-3, etc
117 Belmont & Mitchison (1996)(20) purified Stmn1 protein from calf thymus based on its microtubule depolymerizing activity in vitro (20), and many other examples in the text. Avoid placing reference numbers contiguous to year of publication. Place at the end ot the sentence to conform to standard practice.
156 kainite -> kainate
161 JNK-targeted serines of Stmn2
164 Stmn2 abundance in axons
181 neuronal health maintenance
192 diminish Stmn2 localization
193 axons shafts
194 Dorsal Root Ganglion (DRG)
201 conferring sensitivity of Stmn2
202 with using
204 comigrate reconsider co-localize
208. and thus liberating ?
227 beta-amyloid peptides accumulation -> accumulation of beta-amyloid peptides
232 pseudo- phosphorylation of Stmn2 ??
236 growth cones (63)
236 calcium-permeable
236 They -> Greka et al.
242 Notably, there is selectivity in cargo regulation because synaptotagmin trafficking is unaffected by Stmn2 manipulation. Provide more detail on synaptotagmin and its function
247 between their palmitoylation
250. trans-Golgi, (insert komma)
252 how they regulate interaction with molecular motors
257. Protecting axon health axons
258 functional connectivity of neurons
258 may improve patient outcome in neurodegenerative diseases
259 neuronal health. see above
259 Discoveries in from
266 phosphorylation-resistant
267 axon-protective
269 increasesd
271 Stmn2 membrane-association
272 et al., no komma
273 Stmn2 palmitoylation
275 axon segments , severed axon segments ?
276 axon-protective
278 membrane association of Stmn
284 Stmn2 roles -> The role of Stmn2
285 membrane association of Stmn2
288 layer in axon integrity -> aspect of axon integrity ?
296 pro-regenerative genes
303 motor paralysis
308 ALS motor neurons specify as pointed out above
310 Reduced levels of nuclear TDP-43 interferes with splicing of over 1,500 RNAs having a massive impact on global RNA metabolism
323 Cryptic Stmn2 splicing is also detected
325 Stmn2 transcript variants produced by TDP-43 loss resulting from TDP-43 mislocalization
332 gene therapy technology can could be used to introduce a Stmn2 variant
333 For instance, or As an illustration , splice-modifying ...
347 body knockout mice -> constitutive Stmn2 knockout abolishing Stmn2 expression in all body tissues of mice
361 both of which
362 Altogether, these studies show that Stmn2
363 ALS treatments
368 Stathmin-depolymerizing activity
375 As relays between kinase signaling and the pool of free tubulin heterodimer ...
rephrase
376 local tubulin polymerization in neurons check/add
381 microtubule-binding
386 most logical. not logic ''most straightforard
390 tubulin polymerization and depolymerization
393 microtubule severing proteins
404 connect
406 APTs spell out 406 Acyl-protein thioesterases (APTs)
407 co-residents rephrase
409 co-migration co-localization
416 New surprises in this protein family rephrase Advances in the understanding of this protein family or something similar
424 Stmn2 populations proteins
433 kinesin motor proteins or kinesin motors (plural)
439 meet local needs . needs of what ?
442 tubulin polymerization and depolymerization
450 escalating motor disability -> progressive motor dysfunction