Deconstructing the molecular genetics behind the PINK1/Parkin axis in Parkinson’s disease using Drosophila melanogaster as a model organism

Abstract Background Parkinson’s disease (PD) is a multifactorial neurodegenerative disorder marked by the death of nigrostriatal dopaminergic neurons in response to the compounding effects of oxidative stress, mitochondrial dysfunction and protein aggregation. Transgenic Drosophila models have been...

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Autores principales:	Suchita Ganesan, Venkatachalam Deepa Parvathi
Formato:	article
Lenguaje:	EN
Publicado:	SpringerOpen 2021
Materias:	Parkinson’s disease PINK1 Parkin Drosophila melanogaster Mitochondrial dynamics Apoptosis Medicine (General) R5-920 Genetics QH426-470
Acceso en línea:	https://doaj.org/article/1ed0f355987d42caa80dd5f35aa31a8c
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spelling	oai:doaj.org-article:1ed0f355987d42caa80dd5f35aa31a8c2021-11-28T12:05:13ZDeconstructing the molecular genetics behind the PINK1/Parkin axis in Parkinson’s disease using Drosophila melanogaster as a model organism10.1186/s43042-021-00208-22090-2441https://doaj.org/article/1ed0f355987d42caa80dd5f35aa31a8c2021-11-01T00:00:00Zhttps://doi.org/10.1186/s43042-021-00208-2https://doaj.org/toc/2090-2441Abstract Background Parkinson’s disease (PD) is a multifactorial neurodegenerative disorder marked by the death of nigrostriatal dopaminergic neurons in response to the compounding effects of oxidative stress, mitochondrial dysfunction and protein aggregation. Transgenic Drosophila models have been used extensively to decipher the underlying genetic interactions that exacerbate neural health in PD. Autosomal recessive forms of the disease have been linked to mutations in the serine/threonine kinase PINK1(PTEN-Induced Putative Kinase 1) and E3 ligase Parkin, which function in an axis that is conserved in flies. This review aims to probe the current understanding of PD pathogenesis via the PINK1/Parkin axis while underscoring the importance of several molecular and pharmacologic rescues brought to light through studies in Drosophila. Main body Mutations in PINK1 and Parkin have been shown to affect the axonal transport of mitochondria within dopaminergic neurons and perturb the balance between mitochondrial fusion/fission resulting in abnormal mitochondrial morphology. As per studies in flies, ectopic expression of Fwd kinase and Atg-1 to promote fission and mitophagy while suppressing fusion via MUL1 E3 ligase may aid to halt mitochondrial aggregation and prolong the survival of dopaminergic neurons. Furthermore, upregulation of Hsp70/Hsp90 chaperone systems (Trap1, CHIP) to target misfolded mitochondrial respiratory complexes may help to preserve their bioenergetic capacity. Accumulation of reactive oxygen species as a consequence of respiratory complex dysfunction or antioxidant enzyme deficiency further escalates neural death by inducing apoptosis, lipid peroxidation and DNA damage. Fly studies have reported the induction of canonical Wnt signalling to enhance the activity of transcriptional co-activators (PGC1α, FOXO) which induce the expression of antioxidant enzymes. Enhancing the clearance of free radicals via uncoupling proteins (UCP4) has also been reported to ameliorate oxidative stress-induced cell death in PINK1/Parkin mutants. Conclusion While these novel mechanisms require validation through mammalian studies, they offer several explanations for the factors propagating dopaminergic death as well as promising insights into the therapeutic importance of transgenic fly models in PD.Suchita GanesanVenkatachalam Deepa ParvathiSpringerOpenarticleParkinson’s diseasePINK1ParkinDrosophila melanogasterMitochondrial dynamicsApoptosisMedicine (General)R5-920GeneticsQH426-470ENEgyptian Journal of Medical Human Genetics, Vol 22, Iss 1, Pp 1-20 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Parkinson’s disease PINK1 Parkin Drosophila melanogaster Mitochondrial dynamics Apoptosis Medicine (General) R5-920 Genetics QH426-470
spellingShingle	Parkinson’s disease PINK1 Parkin Drosophila melanogaster Mitochondrial dynamics Apoptosis Medicine (General) R5-920 Genetics QH426-470 Suchita Ganesan Venkatachalam Deepa Parvathi Deconstructing the molecular genetics behind the PINK1/Parkin axis in Parkinson’s disease using Drosophila melanogaster as a model organism
description	Abstract Background Parkinson’s disease (PD) is a multifactorial neurodegenerative disorder marked by the death of nigrostriatal dopaminergic neurons in response to the compounding effects of oxidative stress, mitochondrial dysfunction and protein aggregation. Transgenic Drosophila models have been used extensively to decipher the underlying genetic interactions that exacerbate neural health in PD. Autosomal recessive forms of the disease have been linked to mutations in the serine/threonine kinase PINK1(PTEN-Induced Putative Kinase 1) and E3 ligase Parkin, which function in an axis that is conserved in flies. This review aims to probe the current understanding of PD pathogenesis via the PINK1/Parkin axis while underscoring the importance of several molecular and pharmacologic rescues brought to light through studies in Drosophila. Main body Mutations in PINK1 and Parkin have been shown to affect the axonal transport of mitochondria within dopaminergic neurons and perturb the balance between mitochondrial fusion/fission resulting in abnormal mitochondrial morphology. As per studies in flies, ectopic expression of Fwd kinase and Atg-1 to promote fission and mitophagy while suppressing fusion via MUL1 E3 ligase may aid to halt mitochondrial aggregation and prolong the survival of dopaminergic neurons. Furthermore, upregulation of Hsp70/Hsp90 chaperone systems (Trap1, CHIP) to target misfolded mitochondrial respiratory complexes may help to preserve their bioenergetic capacity. Accumulation of reactive oxygen species as a consequence of respiratory complex dysfunction or antioxidant enzyme deficiency further escalates neural death by inducing apoptosis, lipid peroxidation and DNA damage. Fly studies have reported the induction of canonical Wnt signalling to enhance the activity of transcriptional co-activators (PGC1α, FOXO) which induce the expression of antioxidant enzymes. Enhancing the clearance of free radicals via uncoupling proteins (UCP4) has also been reported to ameliorate oxidative stress-induced cell death in PINK1/Parkin mutants. Conclusion While these novel mechanisms require validation through mammalian studies, they offer several explanations for the factors propagating dopaminergic death as well as promising insights into the therapeutic importance of transgenic fly models in PD.
format	article
author	Suchita Ganesan Venkatachalam Deepa Parvathi
author_facet	Suchita Ganesan Venkatachalam Deepa Parvathi
author_sort	Suchita Ganesan
title	Deconstructing the molecular genetics behind the PINK1/Parkin axis in Parkinson’s disease using Drosophila melanogaster as a model organism
title_short	Deconstructing the molecular genetics behind the PINK1/Parkin axis in Parkinson’s disease using Drosophila melanogaster as a model organism
title_full	Deconstructing the molecular genetics behind the PINK1/Parkin axis in Parkinson’s disease using Drosophila melanogaster as a model organism
title_fullStr	Deconstructing the molecular genetics behind the PINK1/Parkin axis in Parkinson’s disease using Drosophila melanogaster as a model organism
title_full_unstemmed	Deconstructing the molecular genetics behind the PINK1/Parkin axis in Parkinson’s disease using Drosophila melanogaster as a model organism
title_sort	deconstructing the molecular genetics behind the pink1/parkin axis in parkinson’s disease using drosophila melanogaster as a model organism
publisher	SpringerOpen
publishDate	2021
url	https://doaj.org/article/1ed0f355987d42caa80dd5f35aa31a8c
work_keys_str_mv	AT suchitaganesan deconstructingthemoleculargeneticsbehindthepink1parkinaxisinparkinsonsdiseaseusingdrosophilamelanogasterasamodelorganism AT venkatachalamdeepaparvathi deconstructingthemoleculargeneticsbehindthepink1parkinaxisinparkinsonsdiseaseusingdrosophilamelanogasterasamodelorganism
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Deconstructing the molecular genetics behind the PINK1/Parkin axis in Parkinson’s disease using Drosophila melanogaster as a model organism

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