title: Poly(ADP-ribose)polymerase-1 hyperactivation in neurodegenerative diseases: The death knell tolls for neurons.
abstract: Neurodegeneration is a salient feature of chronic refractory brain disorders like Alzheimer's, Parkinson's, Huntington's, amyotropic lateral sclerosis and acute conditions like cerebral ischemia/reperfusion etc. The pathological protein aggregates, mitochondrial mutations or ischemic insults typifying these disease conditions collude with and intensify existing oxidative stress and attendant mitochondrial dysfunction. Interlocking these mechanisms is poly(ADP-ribose) polymerase (PARP-1) hyperactivation that invokes a distinct form of neuronal cell death viz., 'parthanatos'. PARP-1, a typical 'moonlighting protein' by virtue of its ability to poly(ADP-ribosyl)ate a plethora of cellular proteins exerts diverse functions that impinge significantly on cellular processes. In addition, its interactions with various nuclear proteins like transcription factors and chromatin modifiers elicit varied transcriptional outcomes that wield pathological cellular responses. Further, emerging leitmotifs like mitochondrial and nucleolar PARPs and the novel aspects of gene expression regulation by PARP-1 and poly(ADP-ribosyl)ation can provide a holistic view of PARP-1's influence on cell vitality. In this review, we discuss the pathological underpinnings of PARP-1, with a special emphasis on mitochondrial dysfunction and cell death subroutines, in the realm of neurodegeneration. This would provide a deeper insight into the functions of PARP-1 in neurodegenerative conditions that would enable the development of more effective therapeutic strategies.
authors.affiliation: Laboratory of Neuroscience, Department of Biotechnology & Bioinformatics, School of Life Sciences, University of Hyderabad, Hyderabad 500046, India.
authors.forename: Parimala
authors.initials: P
authors.lastname: Narne
authors.affiliation: Laboratory of Neuroscience, Department of Biotechnology & Bioinformatics, School of Life Sciences, University of Hyderabad, Hyderabad 500046, India.
authors.forename: Vimal
authors.initials: V
authors.lastname: Pandey
authors.affiliation: Laboratory of Neuroscience, Department of Biotechnology & Bioinformatics, School of Life Sciences, University of Hyderabad, Hyderabad 500046, India.
authors.forename: Praveen Kumar
authors.initials: PK
authors.lastname: Simhadri
authors.affiliation: Laboratory of Neuroscience, Department of Biotechnology & Bioinformatics, School of Life Sciences, University of Hyderabad, Hyderabad 500046, India. Electronic address: prakashbabuphanithi@gmail.com.
authors.forename: Prakash Babu
authors.initials: PB
authors.lastname: Phanithi
mesh_terms: D000818:Animals; D002466:Cell Nucleolus / Q000201:enzymology; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000201:enzymology* / Q000473:pathology*; D009474:Neurons / Q000201:enzymology* / Q000473:pathology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D060066:Protein Interaction Maps
chemical_list: D011065:Poly(ADP-ribose) Polymerases
keywords: AIF translocation; Mitochondrial dysfunction; Neurodegeneration; PARP-1; PARylation; Parthanatos