{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T10:46:38Z","timestamp":1782297998140,"version":"3.54.5"},"update-to":[{"DOI":"10.12688\/f1000research.170090.1","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T00:00:00Z","timestamp":1781740800000}},{"DOI":"10.12688\/f1000research.170090.2","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T00:00:00Z","timestamp":1781740800000}}],"reference-count":32,"publisher":"F1000 Research Ltd","license":[{"start":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T00:00:00Z","timestamp":1781740800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["f1000research.com"],"crossmark-restriction":false},"short-container-title":["F1000Res"],"abstract":"<ns5:p>\n                    Abstract Parkinson\u2019s disease (PD) is a widespread and progressively debilitating neurodegenerative disorder with a growing global prevalence. While most cases are sporadic, loss-of-function variants in the\n                    <ns5:italic>PINK1<\/ns5:italic>\n                    gene are a primary cause of autosomal recessive early-onset PD. This review critically explores the molecular mechanisms linking PINK1 dysfunction to PD, with a specific focus on the kinase\u2019s role in phosphorylating Ubiquitin and Parkin at the conserved Serine 65 (Ser65) residue. We discuss how this phosphorylation event acts as a molecular switch to recruit the novel autophagy receptors Optineurin (OPTN) and NDP52, thereby initiating mitophagy\u2014a process often disrupted by pathogenic variants. Furthermore, we examine the emerging role of PINK1 in suppressing neuroinflammation via the STING pathway and evaluate the translational potential of targeting these molecular checkpoints for therapeutic intervention. These insights lay the groundwork for developing precision medicine strategies to address the urgent need for effective PD treatments.\n                  <\/ns5:p>","DOI":"10.12688\/f1000research.170090.3","type":"journal-article","created":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T13:54:05Z","timestamp":1781790845000},"page":"1138","update-policy":"https:\/\/doi.org\/10.12688\/f1000research.crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Mechanisms Associated with PINK1 Variants in Parkinson's Disease"],"prefix":"10.12688","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5507-2680","authenticated-orcid":false,"given":"Hanliang","family":"Dan","sequence":"first","affiliation":[{"name":"School of Biology, Faculty of Applied Sciences Shah Alam Seksyen 2, 40450 Selangor Universiti Teknologi MARA, UiTM"},{"name":"Centre for Chemical Synthesis and Polymer Technology, Institute of Science Shah Alam Seksyen 2, 40450 Selangor Universiti Teknologi MARA, UiTM"},{"name":"Guilin Guangxi 541002 Nanxishan Hospital of Guangxi Zhuang Autonomous Region (The Second People's Hospital of Guangxi Zhuang Autonomous Region)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohui","family":"Huang","sequence":"additional","affiliation":[{"name":"Guangxi Key Laboratory of Multimodal Biomarkers and Precision Diagnosis, College of Medical Laboratory and Biotechnology Guilin Guangxi 541004 Guilin Medical University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4158-6768","authenticated-orcid":false,"given":"Zheng","family":"Liu","sequence":"additional","affiliation":[{"name":"Guangxi Key Laboratory of Multimodal Biomarkers and Precision Diagnosis, College of Medical Laboratory and Biotechnology Guilin Guangxi 541004 Guilin Medical University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bing","family":"Wei","sequence":"additional","affiliation":[{"name":"Guilin Medical University Guilin Guangxi 541004 Guangxi Key Laboratory of Tumor Immunology and Microenvironment Regulation, Department of Basic Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maslinda","family":"Musa","sequence":"additional","affiliation":[{"name":"School of Biology, Faculty of Applied Sciences Shah Alam Seksyen 2, 40450 Selangor Universiti Teknologi MARA, UiTM"},{"name":"Centre for Chemical Synthesis and Polymer Technology, Institute of Science Shah Alam Seksyen 2, 40450 Selangor Universiti Teknologi MARA, UiTM"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"2560","published-online":{"date-parts":[[2026,6,18]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"939-953","DOI":"10.1016\/S1474-4422(18)30295-3","article-title":"Global, regional, and national burden 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Hertz","year":"2013","journal-title":"Cell."},{"key":"ref31","doi-asserted-by":"publisher","first-page":"370-375","DOI":"10.1038\/nature13418","article-title":"The mitochondrial deubiquitinase USP30 opposes parkin-mediated mitophagy.","volume":"510","author":"B Bingol","year":"2014","journal-title":"Nature."},{"key":"ref32","doi-asserted-by":"publisher","first-page":"7295","DOI":"10.1038\/s41467-023-42876-1","article-title":"Knockout or inhibition of USP30 protects dopaminergic neurons in a Parkinson\u2019s disease mouse model.","volume":"14","author":"T Fang","year":"2023","journal-title":"Nat Commun."}],"container-title":["F1000Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/f1000research.com\/articles\/14-1138\/v3\/xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/f1000research.com\/articles\/14-1138\/v3\/pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/f1000research.com\/articles\/14-1138\/v3\/iparadigms","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T09:54:11Z","timestamp":1782294851000},"score":1,"resource":{"primary":{"URL":"https:\/\/f1000research.com\/articles\/14-1138\/v3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,18]]},"references-count":32,"URL":"https:\/\/doi.org\/10.12688\/f1000research.170090.3","relation":{"has-version":[{"id-type":"doi","id":"10.12688\/f1000research.170090.2","asserted-by":"subject"},{"id-type":"doi","id":"10.12688\/f1000research.170090.1","asserted-by":"subject"}],"has-review":[{"id-type":"doi","id":"10.5256\/f1000research.202783.r494991","asserted-by":"subject"},{"id-type":"doi","id":"10.5256\/f1000research.202783.r494991","asserted-by":"object"}]},"ISSN":["2046-1402"],"issn-type":[{"value":"2046-1402","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,18]]},"assertion":[{"value":"Indexed","URL":"https:\/\/f1000research.com\/articles\/14-1138\/v3#article-reports","order":0,"name":"referee-status","label":"Referee status","group":{"name":"current-referee-status","label":"Current Referee Status"}},{"value":"10.5256\/f1000research.187509.r440954, Eman Ezzeldien Mohamed, Beni-Suef University, Beni-Suef, 29 Dec 2025, version 1, 1 approved, 1 not approved","URL":"https:\/\/f1000research.com\/articles\/14-1138\/v1#referee-response-440954","order":0,"name":"referee-response-440954","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>Zheng Liu<\/b>; \n<i>Posted: 15 Mar 2026<\/i>; This manuscript addresses an important topic by reviewing the mechanisms linking PINK1 mutations to Parkinson\u2019s disease. The review is generally well-referenced and provides informative coverage of mitochondrial dysfunction, autophagy, and oxidative stress.  1. The Introduction should more clearly define the scope of the review and highlight existing knowledge gaps. Several sections remain largely descriptive, and greater critical analysis of the literature is needed.  Respond: We agree. We revised the Introduction's final paragraph to clearly define the review's scope and highlight knowledge gaps, specifically PINK1's non-mitophagic roles in innate immunity. We also cited seminal studies on the gut-brain axis and inflammation, such as Matheoud et al. (2019), to enhance our critical analysis.  2. the Review should better explain the mechanistic reasons behind the reported pathological outcomes.  Respond: Thank you for the suggestion. We significantly deepened the mechanistic discussions. In Section 3, we detail how specific variants fail to phosphorylate Ubiquitin\/Parkin at Ser65. In Section 4.2, we explain how this failure blocks the recruitment of key autophagy receptors (OPTN and NDP52), leading to the accumulation of ROS-producing mitochondria that mechanically drives neurodegeneration.  3. the clinical and translational relevance of PINK1 mutations could be more explicitly addressed. Improving integration between the figure and the main text would also enhance clarity.  Respond: We appreciate these suggestions and made two major updates: 1.Translational Relevance: We added a new section (Section 4.4: Therapeutic Implications) exploring precision medicine strategies, highlighting neo-substrates (e.g., Kinetin) and USP30 inhibitors. 2. Figure Integration: We rewrote the legend for Figure 1 so it fully explains the mechanisms and stands alone. We also improved its integration by citing it at key mechanistic junctures (e.g., Sections 2 and 4.2) in the main text.","URL":"https:\/\/f1000research.com\/articles\/14-1138\/v3#referee-comment-15688","order":1,"name":"referee-comment-15688","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.5256\/f1000research.187509.r425648, Ryan L Davis, University of Sydney, Sydney, Sydney, 30 Dec 2025, version 1, 1 approved, 1 not approved","URL":"https:\/\/f1000research.com\/articles\/14-1138\/v1#referee-response-425648","order":2,"name":"referee-response-425648","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>Zheng Liu<\/b>; \n<i>Posted: 15 Mar 2026<\/i>; Mechanisms Associated with PINK1 Mutations in Parkinson's Disease ABSTRACT Gene names should be in italics PINK1 and PTEN induced kinase 1 are the HGNC approved symbol and name \u2013 perhaps include the stable ID; HGNC:14581 \n<b>Respond:<\/b> In accordance with the reviewer's suggestion, we have italicized all gene names (e.g.,\n<i> PINK1<\/i>) throughout the manuscript to distinguish them from their protein products. Additionally, we have included the HGNC approved symbol, full name, and the stable ID (HGNC:14581) at the first mention of the gene in the Introduction.  \u201cCentral to its pathogenesis is the \n<i>PINK1<\/i> gene\u2026\u201d is a broad overgeneralisation that makes it seem like \n<i>PINK1<\/i> is the only cause of PD and not more specific to monogenic early-onset familial PD. \n<b>Respond:<\/b> We agree with the reviewer that the original statement was too broad. We have revised the text, \u201cWhile most cases are sporadic, loss-of-function variants in the PINK1 gene are a primary cause of autosomal recessive early-onset PD.\u201d. We have also clarified that studying\n<i> PINK1 <\/i>provides a critical window into mitochondrial dysfunction, which is a shared feature in both familial and sporadic PD.  INTRODUCTION Parkinson\u2019s disease is defined as (PD) in the first line, but the abbreviation is not consistently used thereafter Respond: We appreciate the reviewer's attention to detail. We have corrected this throughout the manuscript. Following the initial definition in the first sentence of the Introduction, the abbreviation &quot;PD&quot; is now used consistently in place of the full term.  There is a lot of information in the first paragraph that is not appropriately attributed to the original publications. Even a WHO report is mentioned but not referenced. Only the last sentence has an appropriate citation. \n<b>Respond: <\/b>We apologize for the insufficient citations in the original draft. We have now added the appropriate references for the epidemiological data and specifically cited the World Health Organization (WHO) report on Parkinson\u2019s disease as requested. &nbsp;  \u201cWithin four years of diagnosis, there is a rapid and nearly complete loss of dopaminergic markers in the dorsal striatum\u201d neglects the fact that there is a long pro-drome with progressive neurodegeneration. It also reflects the older onset progression of PD and not the early onset monogenic form that is relevant to PINK1. Might need to compare and contrast late vs early onset and idiopathic vs familial. \n<b>Respond: <\/b>We appreciate this insightful comment. In the revised Introduction (Paragraph 2), we have addressed this by: 1. Acknowledging the prolonged prodromal phase that precedes motor symptoms. 2. Explicitly distinguishing the clinical phenotype of \n<i>PINK1<\/i>-linked PD from idiopathic cases. We now clarify that\n<i> PINK1<\/i> variants are associated with early-onset Parkinsonism (often before age 45) and a sustained response to levodopa, contrasting this with the older-onset progression of sporadic PD as suggested.  Please check whether \u2018variant\u2019 is more appropriate than \u2018mutation\u2019 Respond: We completely agree with the reviewer. In accordance with current genetic nomenclature guidelines, we have globally replaced the term &quot;mutation&quot; with &quot;variant&quot; throughout the manuscript to describe pathogenic genetic alterations.  Not sure how appropriate it is to reference a review for core research results. Reference the original citations where possible. Some citations are quite old. Suggest searching for more contemporary research evidencing the claims made. \n<b>Respond:<\/b> We appreciate this valid critique. We have comprehensively audited our reference list. We have removed over-reliance on older review articles and replaced them with highly relevant, contemporary primary research articles.  \u201cPINK1 (PTEN-induced putative kinase 1) mutations represent the second most common cause of autosomal recessive early-onset Parkinson\u2019s disease (EOPD), following Parkin mutations\u201d suggests you are talking about the genes, and therefore PINK1 should be in italics and Parkin should be PRKN. \n<b>Respond:<\/b> PINK1 has been in italics and Parkin has been changed to PRKN.  2. DIVERSITY OF PINK1 MUTATIONS \u201cMutations in the PINK1 gene are strongly linked to PD\u201d is suggestive that this is not definitive but rather remains controversial, which certainly isn\u2019t the case. It would seem that this sentence is perfunctory. \n<b>Respond:<\/b> the sentence has been rewrote.  First paragraph has no references to support the information presented. \n<b>Respond:<\/b> the references has been added to the first paragraph.  Perhaps the second paragraph could be contextualised with the current extent of PINK1 variants and then perhaps that might help address the next comment. \n<b>Respond:<\/b> Thank you for the suggestion. I agree that providing a broader context on the current landscape of PINK1 variants\u2014such as the distinction between pathogenic mutations and benign variants, or the known mutation hotspots\u2014would strengthen the paragraph. This additional detail would not only ground the discussion but also serve as a natural bridge to the subsequent point in the comment.&quot;  If the variants have been known for over 20 years how do they \u201c\u2026offers valuable guidance for the development of future therapeutic interventions.\u201d? \n<b>Respond:<\/b> We have extensively revised this section (now Section 3) to address the reviewer's concerns regarding clarity, referencing, and logical flow: 1. Definitive Language: We have removed the tentative phrasing and now explicitly state that pathogenic variants cause a loss of function, disrupting the neuroprotective response. 2. References Added: We have added the necessary citations to the opening paragraph to support the historical identification and structural clustering of these variants [Valente et al., 2004; Scholten et al., 2020]. 3. Updated Context: We have updated the text to reflect the current landscape, noting that over 70 variants have been cataloged, and we have categorized them by mechanism (kinase inactivation vs. protein instability). 4. Removed Outdated Conclusion: We have removed the generic statement about &quot;future therapeutic guidance.&quot; Instead, the section now concludes by summarizing the specific pathological outcome of these variants: the failure to sense mitochondrial depolarization and initiate mitophagy.  I would almost introduce normal PINK1 activity and physiology before talking about variants and how the dysfunction of the molecule underpins pathogenesis. As it stands, we\u2019re learning about variants before really understanding the normal function and mechanisms of PINK1 activity. \n<b>Respond:<\/b> We are grateful for this excellent suggestion. We agree that a solid understanding of the physiological function of PINK1 is a prerequisite for discussing its pathogenicity. In the revised manuscript, we have inserted a new section entitled &quot;Section 2. Physiological Role and Regulation of PINK1&quot; immediately following the Introduction. In this section, we now detail: 1. The canonical import of PINK1 into healthy mitochondria via the TOM\/TIM complexes. 2. Its proteolytic processing by MPP and PARL. 3. Its rapid degradation via the N-end rule pathway. 4. Its function as a molecular sensor for mitochondrial membrane potential. This new section provides the necessary biological context before we introduce the pathogenic variants in the subsequent section (now Section 3).3. PINK1 AND THE PATHOGENESIS OF PD  3.1 PINK1 MUTATIONS AND MITOCHONDRIAL PHOSPHORYLATION The section title suggests PINK1 phosphorylates mitochondria. Instead, a more accurate section title might be PINK1 mutations and target protein phosphorylation \n<b>Respond: <\/b>We agree with the reviewer that the original title was imprecise. In the revised manuscript, we have renamed this section (now Section 4.1) to &quot;\n<i>PINK1<\/i> Variants Impair Phosphorylation of Downstream Substrates.&quot; This title more accurately reflects the mechanistic reality that PINK1 targets specific proteins\u2014namely Parkin and Ubiquitin\u2014rather than the mitochondrial organelle as a whole.  Figure legends should explain a figure as if it were standalone. Figure 1 only has a figure legend title and no supporting description of what is depicted. From author instructions for Reviews: \u201cTitles and legends: Each figure or table should have a concise title of no more than 15 words. A legend for each figure and table should also be provided that briefly describes the key points and explains any symbols and abbreviations used. The legend should be sufficiently detailed so that the figure or table can stand alone from the main text.\u201d This is currently not the case for Figure 1. \n<b>Respond:<\/b> We apologize for this omission. We have provided a comprehensive, standalone legend for Figure 1 that thoroughly explains the depicted mechanisms, including basal turnover, mitophagy initiation (highlighting OPTN\/NDP52), and the disease state. All abbreviations used in the figure are now explicitly defined in the legend. Additionally, we have ensured that Figure 1 is properly cited and integrated within the relevant mechanistic sections of the main text to guide the reader effectively.  3.2 PINK1 MUTATIONS AND ABNORMAL MITOPHAGY PATHWAYS Parkin is introduced here as if it is the first time it is introduced with its function etc. yet it appears in all sections above While p62 was originally the best characterised autophagy receptor for Parkin-mediated mitophagy, there are several others that have been identified as being more prominent, including optineurin and NDP52. While NBR1 and TAX1BP1 are less prominent like p62. \n<b>Respond:<\/b> We are grateful to the reviewer for their careful reading and for pointing out this critical evolution in the field. We have made two major revisions to this section (now Section 4.2) to fully address these concerns: 1. Removal of redundant Parkin introduction: We apologize for the redundancy. With the addition of the new &quot;Section 2. Physiological Role and Regulation of PINK1&quot; earlier in the manuscript, Parkin's baseline function is now appropriately introduced upon its first mention. We have carefully revised Section 4.2 to remove the repetitive introduction of Parkin, ensuring a smoother logical flow. 2. Updating the mitophagy receptor consensus: We have significantly revised the text to reflect the current consensus on autophagy receptors. As the reviewer correctly pointed out, we now explicitly state that Optineurin (OPTN) and NDP52 are the primary receptors essential for mitophagy. We also briefly acknowledge that p62, NBR1, and TAX1BP1 play less prominent roles. Furthermore, we now detail how PINK1-mediated phosphorylation of ubiquitin serves as the specific signal to recruit OPTN and NDP52. Key citations have been added to support this updated, contemporary perspective.OVERALL  Overall I found this short review to provide limited insight into the role of PINK1 in Parkinson\u2019s disease with often outdated or incomplete supporting literature. PINK1 and Parkin have considerable influence outside of mitophagy, for instance PINK1 and Parkin were shown to be central to innate immunity in a knockout model where PD was induced by intestinal infection. Additionally, mitochondrial dysfunction can be the cause or corollary in PD and while this review takes the simplistic and repeated view of PINK1 and Parkin centrality to mitophagy, it is a limited view and negates the peripheral complexities and multifaceted nature of PD pathogenesis. As such, this review does nothing more than to reiterate information that have been presented ad nauseum without opinion or insight into the potential for therapeutic treatment that has thus far failed and remains an endeavour for the entire field. While the review is generally well written it lacks originality in insight and opinion that would drive the field in a particular direction, as a good review should do. As a result, I think this review is severely lacking and adds little to the literature that hasn\u2019t already been presented numerous times previously. \n<b>Respond: <\/b>We are deeply grateful for this profound and constructive critique, which has fundamentally elevated the quality of our manuscript. We fully agree that our previous draft was too narrowly focused on canonical mitophagy and lacked forward-looking translational insights. To address this, we have made substantial additions: 1. Expansion Beyond Mitophagy (Innate Immunity &amp; Gut-Brain Axis): We have added a completely new section (Section 4.3: Beyond Mitophagy:\n<i> <\/i>PINK1 and Neuroinflammation). As astutely suggested by the reviewer, we now extensively discuss the role of PINK1 as a critical immunological checkpoint. We specifically highlight the seminal Nature study demonstrating that intestinal infection triggers autoimmune mechanisms in \n<i>Pink1<\/i>-knockout mice via mitochondrial antigen presentation (Matheoud et al., 2019) , as well as the activation of the cGAS-STING pathway. 2. Translational Relevance and Therapeutic Insight: We have added another new section (Section 4.4: Therapeutic Implications) to provide the missing &quot;insight and opinion&quot; on drug development. We critically evaluate novel precision medicine strategies, specifically highlighting the amplification of kinase activity (via Kinetin) and the promising strategy of bypassing mitophagy blockades using USP30 inhibitors. 3. We believe these major revisions transform the manuscript from a mere descriptive summary into a critical, forward-looking review that offers a new framework for understanding PINK1 pathogenesis and developing targeted therapies.","URL":"https:\/\/f1000research.com\/articles\/14-1138\/v3#referee-comment-15690","order":3,"name":"referee-comment-15690","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.5256\/f1000research.202783.r494991, DOMENICO PRATICO, Department of Neural Sciences, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania, 24 Jun 2026, version 3, indexed","URL":"https:\/\/f1000research.com\/articles\/14-1138\/v3#referee-response-494991","order":4,"name":"referee-response-494991","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"The author(s) declared that no grants were involved in supporting this work","order":5,"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"}]}}