The Effect of Aggregated Alpha Synuclein on Synaptic and Axonal Proteins in Parkinson’s Disease—A Systematic Review

Round 1

Reviewer 1 Report

This papers studied the role of aggregated α-synuclein on synaptic and axonal proteins in Parkinson’s disease models. It summarized different forms of α-synuclein, stratified the research findings to explore effects of α-synuclein on  synaptic proteins and axonal proteins. The paper supported the hypothesis that the aggregation and mutations of α-synuclein dysregulates or redistributes synaptic and axonal transport proteins. It also can guide new treatment approach that focuses on targeting the underlying mechanisms of PD such as neuronal degeneration, rather than those that just provide symptomatic relief.

There are some problems, which must be solved before it is considered for publication.

1. There were too many variables in the studies included in this review which made it challenging to ascertain what effect α-synuclein had quantitatively on the expression of synaptic and axonal proteins.

2. There are some spelling errors in the manuscript. Please check the manuscript carefully.

3. The introduction should be supplemented more, such as the definition or function of “SNARE-complex”.

4. Please check the citation of table 1 and 2 (not table 1.1 and table 1.2 in page 2)

5. Page 11, the figure 2 consists of 4 parts, but only figure 2a? where is b, c, and d?. In addition, authors should add the figure legend.

Author Response

Reviewer 1:

This papers studied the role of aggregated α-synuclein on synaptic and axonal proteins in Parkinson’s disease models. It summarized different forms of α-synuclein, stratified the research findings to explore effects of α-synuclein on  synaptic proteins and axonal proteins. The paper supported the hypothesis that the aggregation and mutations of α-synuclein dysregulates or redistributes synaptic and axonal transport proteins. It also can guide new treatment approach that focuses on targeting the underlying mechanisms of PD such as neuronal degeneration, rather than those that just provide symptomatic relief.

We thank the reviewer for their comments and for the time taken to review our study. We have addressed each of the points raised below.

There are some problems, which must be solved before it is considered for publication. 

1. There were too many variables in the studies included in this review which made it challenging to ascertain what effect α-synuclein had quantitatively on the expression of synaptic and axonal proteins.

We completely agree with the referee, and this was something that came to light having completed this systematic review. We were hoping to be able to conduct a meta-analysis, but this was not possible for this very point. This is something we have mentioned in the text.

2. There are some spelling errors in the manuscript. Please check the manuscript carefully.

We have performed a spell check and made amendments.

3. The introduction should be supplemented more, such as the definition or function of “SNARE-complex”.

As requested, we have added several lines at the end of page 1 (highlighted) on the SNARE complex.

4. Please check the citation of table 1 and 2 (not table 1.1 and table 1.2 in page 2)

This has now been amended to table 1 and 2.

5. Page 11, thefigure 2 consists of 4 parts, but only figure 2a? where is b, c, and d?. In addition, authors should add the figure legend.

This figure has now been amended to include the other labels and legends included.

Reviewer 2 Report

1)      The authors need to consider critical factors like age in the results section. For Instance, reference 44 reported reduced synaptophysin levels, whereas reference 45 showed unchanged synaptophysin for A53T mutant alpha-synuclein overexpressing mice. Reference 44 used samples from postnatal days 14 and 21 transgenic mice, whereas reference 45 used 52-week-old transgenic mice. The authors need to address if the age of the rodent models used to support the trends they observe contributes to changes in the levels of synaptic and axonal proteins. This information could be included in the results they observe age discrepancies or a general comment in the discussion.

2)      Are the post-mortem tissue studies used for this meta-analysis from the same brain region? If not, highlight the results section. Since different brain regions are affected by disease conditions, it will be essential to see if any trend or discrepancies in synaptic or axonal protein levels across the same brain regions could be correlated to the disease condition.

Minor Comments

1)      Check Grammar Line 46-47: “There is a vast network of proteins are at play”

2)      In table 1 Synaptophysin (ref 47), GAP43 (ref 81), SNAP-47 (ref81), and PSD-95 (ref58) does not indicate the patient’s condition.

Author Response

Reviewer 2: 

We thank the reviewer for their comments and for the time taken to review our study. We have addressed each of the points raised below.

• The authors need to consider critical factors like age in the results section. For Instance, reference 44 reported reduced synaptophysin levels, whereas reference 45 showed unchanged synaptophysin for A53T mutant alpha-synuclein overexpressing mice. Reference 44 used samples from postnatal days 14 and 21 transgenic mice, whereas reference 45 used 52-week-old transgenic mice. The authors need to address if the age of the rodent models used to support the trends they observe contributes to changes in the levels of synaptic and axonal proteins. This information could be included in the results they observe age discrepancies or a general comment in the discussion.

This information has now been included in the results and is mentioned in the discussion.

2)     Are the post-mortem tissue studies used for this meta-analysis from the same brain region? If not, highlight the results section. Since different brain regions are affected by disease conditions, it will be essential to see if any trend or discrepancies in synaptic or axonal protein levels across the same brain regions could be correlated to the disease condition.

Table 1 has now been updated to include this information.

Minor Comments 

• Check Grammar Line 46-47: “There is a vast network of proteins are at play”

This error has now been corrected.

• In table 1 Synaptophysin (ref 47), GAP43 (ref 81), SNAP-47 (ref81), and PSD-95 (ref58) does not indicate the patient’s condition.

Table 1 has now been updated to include this information.