HOT
TOPICS
VPS35 and EIF4G1 Interactions and Novel Candidate Genes for PD: From Genes to Pathways and Back Dhungel N, Eleuteri S, Li L, et al. Parkinson’s disease genes VPS35 and EIF4G1 interact genetically and converge on a-Synuclein. Neuron. 2015;85:76-87.
Despite being predominantly considered a sporadic disorder, Parkinson’s disease (PD) has been increasingly associated with a number of different genes. Nevertheless, our understanding of the basic mechanisms contributing to its pathogenesis remains relatively poor. Recently, Dhungel et al.1 used a combination of approaches and model systems to establish functional interactions between the VPS35 and EIF4G1 genes, both of which have been associated with PD, despite the fact that the pathogenicity of the latter has been subsequently debated. Dhungel et al. succeeded in connecting two such genes to a shared cellular pathway involved in surveillance and processing of misfolded proteins,1 which fits with the knowledge that VPS35 is a component of the retromer complex that modulates protein recycling and clearance, and that EIF4G1 is involved in transcription/translation mechanisms. Dhungel et al.1 predicted that EIF4G1 toxicity under conditions of VPS35 deficiency may be caused by loss of retromer function and showed how dysfunctions of this pathway led to the accumulation of protein misfolding.1 The authors further demonstrated that a VPS35 deletion exacerbates a-synuclein accumulation and toxicity, whereas its overexpression is neuroprotective.1 Such a result tested valid both in transgenic mice and in a primary neuron a-synuclein seeding model, the latter finding being particularly intriguing given that the prion-like hypothesis in PD has gained remarkable momentum.2 The current study might therefore imply a key role for the retromer complex in this process. Yet, retromer complex deficits have been also implicated in Alzheimer’s disease.3 Thus, why a specific VPS35 mutation results in a typical PD phenotype has to be determined. Notably, the approach used by Dhungel et al.1 allowed the identification of a number of interacting genes that might serve as candidate genes for future investigations. Among these, SORT1 (the human ortholog of yeast VPS10 encoding the sortilin protein), which has been already linked to other neurodegenerative diseases including frontotemporal
dementia,4 and SYNJ1 (the human homolog of yeast INP53 encoding synaptojanin 1), which has been indeed associated with parkinsonism.5 This supports the efficacy of the approach used by the authors, who validated their results through different models, from yeast to worms to transgenic mice. As the number of PD genes increases, establishing their functional pathways and whether these genes interact with each other will be crucial. Such knowledge would ultimately lead back to the universal a-synuclein–related pathology and hopefully facilitate the development of both reliable biomarkers and pathway-targeted therapeutic interventions for PD. Roberto Erro, MD Sobell Department of Motor Neuroscience and Movement Disorders, UCL, London, UK Dipartimento di Scienze Neurologiche e del Movimento, Universita di Verona, Verona, Italy
References 1.
Dhungel N, Eleuteri S, Li L, et al. Parkinson’s disease genes VPS35 and EIF4G1 interact genetically and converge on asynuclein. Neuron 2015;85:76-87.
2.
Recasens A, Dehay B, Bove J, et al. Lewy body extracts from Parkinson disease brains trigger a-synuclein pathology and neurodegeneration in mice and monkeys. Ann Neurol 2014;75: 351-362.
3.
Seaman MN. The retromer complex: endosomal protein recycling and beyond. J Cell Sci 2012;125:4693-4702.
4.
Hu F, Padukkavidana T, Vægter CB, et al. Sortilin-mediated endocytosis determines levels of the frontotemporal dementia protein, progranulin. Neuron 2010;68:654-667.
5.
Quadri M, Fang M, Picillo M, et al. International Parkinsonism Genetics Network: Mutation in the SYNJ1 gene associated with autosomal recessive, early-onset Parkinsonism. Hum Mutat 2013;34:1208-1215.
-----------------------------------------------------------Relevant conflicts of interest/financial disclosures: Nothing to report. Received: 10 January 2015; Revised: 18 January 2015; Accepted: 26 January 2015 Published online 15 March 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mds.26187
Movement Disorders, Vol. 30, No. 4, 2015
499
TOPICS
VPS35 and EIF4G1 Interactions and Novel Candidate Genes for PD: From Genes to Pathways and Back Dhungel N, Eleuteri S, Li L, et al. Parkinson’s disease genes VPS35 and EIF4G1 interact genetically and converge on a-Synuclein. Neuron. 2015;85:76-87.
Despite being predominantly considered a sporadic disorder, Parkinson’s disease (PD) has been increasingly associated with a number of different genes. Nevertheless, our understanding of the basic mechanisms contributing to its pathogenesis remains relatively poor. Recently, Dhungel et al.1 used a combination of approaches and model systems to establish functional interactions between the VPS35 and EIF4G1 genes, both of which have been associated with PD, despite the fact that the pathogenicity of the latter has been subsequently debated. Dhungel et al. succeeded in connecting two such genes to a shared cellular pathway involved in surveillance and processing of misfolded proteins,1 which fits with the knowledge that VPS35 is a component of the retromer complex that modulates protein recycling and clearance, and that EIF4G1 is involved in transcription/translation mechanisms. Dhungel et al.1 predicted that EIF4G1 toxicity under conditions of VPS35 deficiency may be caused by loss of retromer function and showed how dysfunctions of this pathway led to the accumulation of protein misfolding.1 The authors further demonstrated that a VPS35 deletion exacerbates a-synuclein accumulation and toxicity, whereas its overexpression is neuroprotective.1 Such a result tested valid both in transgenic mice and in a primary neuron a-synuclein seeding model, the latter finding being particularly intriguing given that the prion-like hypothesis in PD has gained remarkable momentum.2 The current study might therefore imply a key role for the retromer complex in this process. Yet, retromer complex deficits have been also implicated in Alzheimer’s disease.3 Thus, why a specific VPS35 mutation results in a typical PD phenotype has to be determined. Notably, the approach used by Dhungel et al.1 allowed the identification of a number of interacting genes that might serve as candidate genes for future investigations. Among these, SORT1 (the human ortholog of yeast VPS10 encoding the sortilin protein), which has been already linked to other neurodegenerative diseases including frontotemporal
dementia,4 and SYNJ1 (the human homolog of yeast INP53 encoding synaptojanin 1), which has been indeed associated with parkinsonism.5 This supports the efficacy of the approach used by the authors, who validated their results through different models, from yeast to worms to transgenic mice. As the number of PD genes increases, establishing their functional pathways and whether these genes interact with each other will be crucial. Such knowledge would ultimately lead back to the universal a-synuclein–related pathology and hopefully facilitate the development of both reliable biomarkers and pathway-targeted therapeutic interventions for PD. Roberto Erro, MD Sobell Department of Motor Neuroscience and Movement Disorders, UCL, London, UK Dipartimento di Scienze Neurologiche e del Movimento, Universita di Verona, Verona, Italy
References 1.
Dhungel N, Eleuteri S, Li L, et al. Parkinson’s disease genes VPS35 and EIF4G1 interact genetically and converge on asynuclein. Neuron 2015;85:76-87.
2.
Recasens A, Dehay B, Bove J, et al. Lewy body extracts from Parkinson disease brains trigger a-synuclein pathology and neurodegeneration in mice and monkeys. Ann Neurol 2014;75: 351-362.
3.
Seaman MN. The retromer complex: endosomal protein recycling and beyond. J Cell Sci 2012;125:4693-4702.
4.
Hu F, Padukkavidana T, Vægter CB, et al. Sortilin-mediated endocytosis determines levels of the frontotemporal dementia protein, progranulin. Neuron 2010;68:654-667.
5.
Quadri M, Fang M, Picillo M, et al. International Parkinsonism Genetics Network: Mutation in the SYNJ1 gene associated with autosomal recessive, early-onset Parkinsonism. Hum Mutat 2013;34:1208-1215.
-----------------------------------------------------------Relevant conflicts of interest/financial disclosures: Nothing to report. Received: 10 January 2015; Revised: 18 January 2015; Accepted: 26 January 2015 Published online 15 March 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mds.26187
Movement Disorders, Vol. 30, No. 4, 2015
499
