{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T05:10:12Z","timestamp":1772169012650,"version":"3.50.1"},"update-to":[{"DOI":"10.12688\/f1000research.27413.1","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2022,1,20]],"date-time":"2022-01-20T00:00:00Z","timestamp":1642636800000}},{"DOI":"10.12688\/f1000research.27413.2","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2022,1,20]],"date-time":"2022-01-20T00:00:00Z","timestamp":1642636800000}}],"reference-count":73,"publisher":"F1000 Research Ltd","license":[{"start":{"date-parts":[[2022,1,20]],"date-time":"2022-01-20T00:00:00Z","timestamp":1642636800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["f1000research.com"],"crossmark-restriction":false},"short-container-title":["F1000Res"],"abstract":"<ns3:p>\n                    <ns3:bold>Background:<\/ns3:bold>\n                    Parkinson\u2019s disease (PD) is characterized by its progression of motor-related symptoms such as tremors, rigidity, slowness of movement, and difficulty with walking and balance. Comorbid conditions in PD individuals include insulin resistance (IR) and narcolepsy-like sleep patterns. The intersecting sleep symptoms of both conditions include excessive daytime sleepiness, hallucinations, insomnia, and falling into REM sleep more quickly than an average person. Understanding of the biological basis and relationship of these comorbid disorders with PD may help with early detection and intervention strategies to improve quality of life.\n                  <\/ns3:p>\n                  <ns3:p>\n                    <ns3:bold>Methods:<\/ns3:bold>\n                    In this study, an integrative genomics and systems biology approach was used to analyze gene expression patterns associated with PD, IR, and narcolepsy in order to identify genes and pathways that may shed light on how these disorders are interrelated. A correlation analysis with known genes associated with these disorders\n                    <ns3:italic>(LRRK2, HLA-DQB1, and HCRT<\/ns3:italic>\n                    ) was used to query microarray data corresponding to brain regions known to be involved in PD and narcolepsy. This includes the hypothalamus, dorsal thalamus, pons, and subcoeruleus nucleus. Risk factor genes for PD, IR, and narcolepsy were also incorporated into the analysis.\n                  <\/ns3:p>\n                  <ns3:p>\n                    <ns3:bold>Results:<\/ns3:bold>\n                    The PD and narcolepsy signaling networks are connected through insulin and immune system pathways. Important genes and pathways that link PD, narcolepsy, and IR are\n                    <ns3:italic>CACNA1C, CAMK1D, BHLHE41, HMGB1,<\/ns3:italic>\n                    and AGE-RAGE.\n                  <\/ns3:p>\n                  <ns3:p>\n                    <ns3:bold>Conclusions:\u00a0<\/ns3:bold>\n                    We have identified the genetic signatures that link PD with its comorbid disorders, narcolepsy and insulin resistance, from the convergence and intersection of dopaminergic, insulin, and immune system related signaling pathways. These findings may aid in the design of early intervention strategies and treatment regimes for non-motor symptoms in PD patients as well as individuals with diabetes and narcolepsy.\n                  <\/ns3:p>","DOI":"10.12688\/f1000research.27413.3","type":"journal-article","created":{"date-parts":[[2022,1,20]],"date-time":"2022-01-20T04:45:10Z","timestamp":1642653910000},"page":"1361","update-policy":"https:\/\/doi.org\/10.12688\/f1000research.crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Narcolepsy in Parkinson's disease with insulin resistance"],"prefix":"10.12688","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8851-6631","authenticated-orcid":false,"given":"Alisha","family":"Chunduri","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6638-202X","authenticated-orcid":false,"given":"Wim 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Hypothalamus and Pons gene expression for key genes.","author":"A Delprato","year":"2021","journal-title":"figshare."}],"container-title":["F1000Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/f1000research.com\/articles\/9-1361\/v3\/xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/f1000research.com\/articles\/9-1361\/v3\/pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/f1000research.com\/articles\/9-1361\/v3\/iparadigms","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,1,20]],"date-time":"2022-01-20T04:45:21Z","timestamp":1642653921000},"score":1,"resource":{"primary":{"URL":"https:\/\/f1000research.com\/articles\/9-1361\/v3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,20]]},"references-count":73,"URL":"https:\/\/doi.org\/10.12688\/f1000research.27413.3","relation":{"has-review":[{"id-type":"doi","id":"10.5256\/f1000research.119947.r120416","asserted-by":"object"},{"id-type":"doi","id":"10.5256\/f1000research.119947.r120417","asserted-by":"object"}]},"ISSN":["2046-1402"],"issn-type":[{"value":"2046-1402","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,20]]},"assertion":[{"value":"Indexed","URL":"https:\/\/f1000research.com\/articles\/9-1361\/v3#article-reports","order":0,"name":"referee-status","label":"Referee status","group":{"name":"current-referee-status","label":"Current Referee Status"}},{"value":"10.5256\/f1000research.30294.r77250, Makoto Hashimoto, Laboratory for Parkinson's disease, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan, 08 Feb 2021, version 1, 3 approved with reservations","URL":"https:\/\/f1000research.com\/articles\/9-1361\/v1#referee-response-77250","order":0,"name":"referee-response-77250","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>Anna Delprato<\/b>; \n<i>Posted: 10 Mar 2021<\/i>; We would like to thank you for taking the time to review our article and providing constructive feedback. We will submit a revised version once we have received all of the reviews.","URL":"https:\/\/f1000research.com\/articles\/9-1361\/v3#referee-comment-6429","order":1,"name":"referee-comment-6429","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>Anna Delprato<\/b>; \n<i>Posted: 29 Sep 2021<\/i>; Reviewer 1 Comorbidity of Parkinson\u2019s disease (PD) with insulin resistance (IR) and narcolepsy-like sleep patterns are frequently described, but the mechanism is unclear.&nbsp; In this study, an integrative genomics and systems biology approach was used to analyze gene expression patterns associated with PD, IR, and narcolepsy to identify genes and pathways that may shed light on how these disorders are interrelated. The results showed that the PD and narcolepsy signaling networks are connected through insulin and immune system pathways. Important genes and pathways that link PD, narcolepsy, and IR were shown to be CACNA1C, CAMK1D, BHLHE41, HMGB1, and AGE-RAGE. The authors concluded that these findings might aid in the design of early intervention strategies and treatment regimes for non-motor symptoms in PD patients as well as individuals with diabetes and narcolepsy. Overall, the results are interesting and clear. I agree that the paper may contribute to the PD research. My comments are as follows:  Reviewer 1 comment: It would be much better if modification of the expression of the identified genes (knockout or overexpression), including CACNA1C, CAMK1D, BHLHE41, HMGB1, and AGE-RAGE, might result in phenotypes related to PD and\/or narcolepsy in cells or animal models.&nbsp; Are there such previous papers? Otherwise, the result of network analysis alone seems&nbsp; Preliminary.  \n<b>Response:<\/b> \n<b>We thank the reviewer for taking the time to provide us constructive feedback on this manuscript. There is in fact a great deal of evidence derived from knockout and cell based studies linking CACNA1C, HMGB1, and AGER\/AGE-RAGE to Parkinson's pathogenesis. CACNA1C is also associated with Circadian rhythm and narcolepsy. In addition, CAMK1D is a component of the calmodulin dependent calcium signaling cascade and there is also support for its role as an interactor of LRRK2, one of the key genes influencing Parkinson\u2019s. HMGB1 and AGER\/AGE-RAGE appear to act in concert mediating inflammatory processes that ultimately lead to neuron cell death via NF-\u03baB signaling. AGER\/AGE-RAGE and LRRK2 are also linked as RAGE proteins are upregulated in LRRK2 G2019S mutant cells. The LRRK2 G2019S mutation is the most common genetic cause of neurodegeneration and PD. The other major gene of interest identified in the ppi network, BHLHE41, is a transcription factor associated with Circadian processes. Variants of BHLHE41 have been implicated in short sleep syndrome and this gene also has a role in immune function. BHLHE41 in addition to CAMK1D, RAGE, and HMGB1 are also implicated in diabetes.&nbsp;<\/b>  \n<b>Details of the supporting studies for the candidate genes as well as the other network genes have been included in the Introduction and Discussion sections of the revised manuscript.<\/b>  Reviewer 1 comment: In the same context, other experiments, such as immunohistochemistry, should be conducted to confirm the expression of these genes at the protein level.  \n<b>Response:<\/b> \n<b>We agree that the above mentioned studies could be useful to further support the results presented here. Regrettably we do not have access to wet lab facilities. Our method of research is based in bioinformatics, systems biology and integrative genomics.&nbsp;<\/b>  \n<b>However, we were able to address your question using legacy datasets from the Human Protein Atlas (https:\/\/www.proteinatlas.org\/) which also contains data for gene expression in mice and pigs and the human database in the Allen Brain Atlas (https:\/\/human.brain-map.org\/microarray\/search).<\/b>  \n<b>Results for gene expression of the key genes in the hypothalamus and pons are as follows: Each of the genes with the exception of AGER were expressed in both the hypothalamus and pons for human, mouse and pig. CACNA1C expression was also confirmed at the protein level by immunocytochemistry in the mouse hypothalamus and pons\/medulla.<\/b>  \n<b>The expression pattern of the key genes in dorsal thalamus and subcoeruleus nucleus data were obtained for humans only and are as follows: HMGB1, AGER, BHLHE41 are expressed in both the dorsal thalamus and subcoeruleus nucleus. CACNA1C is expressed in the dorsal thalamus and is not expressed in the subcoeruleus nucleus CAMK1D was not expressed in either the dorsal thalamus or subcoeruleus nucleus.&nbsp;<\/b>\n<b>These data are have been added to the revised version of the manuscript.<\/b>","URL":"https:\/\/f1000research.com\/articles\/9-1361\/v3#referee-comment-7231","order":2,"name":"referee-comment-7231","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.5256\/f1000research.78075.r97494, Qing Wang, Department of Neurology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China, 21 Oct 2021, version 2, indexed","URL":"https:\/\/f1000research.com\/articles\/9-1361\/v2#referee-response-97494","order":3,"name":"referee-response-97494","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.5256\/f1000research.78075.r97492, Daniel Enterr\u00eda-Morales, Neurobiology Section, Division of Biological Sciences, University of California San Diego, La Jolla, CA, USA, 02 Nov 2021, version 2, indexed","URL":"https:\/\/f1000research.com\/articles\/9-1361\/v2#referee-response-97492","order":4,"name":"referee-response-97492","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>Anna Delprato<\/b>; \n<i>Posted: 02 Jan 2022<\/i>; Thank you for reviewing version 2 of our article and catching these edits. We have incorporated the indicated corrections in a new version.","URL":"https:\/\/f1000research.com\/articles\/9-1361\/v3#referee-comment-7658","order":5,"name":"referee-comment-7658","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"The author(s) declared that no grants were involved in supporting this work","order":6,"name":"grant-information","label":"Grant Information"},{"value":"This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.","order":0,"name":"copyright-info","label":"Copyright"}]}}