Poly(ADP-ribose)polymerase-1 hyperactivation in neurodegenerative diseases: The death knell tolls for neurons

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 typifyi...

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Bibliographic Details
Published in:Seminars in cell & developmental biology 2017-03, Vol.63, p.154-166
Main Authors: Narne, Parimala, Pandey, Vimal, Simhadri, Praveen Kumar, Phanithi, Prakash Babu
Format: Article
Language:English
Subjects:
AIF translocation
Animals
Cell Nucleolus - enzymology
Humans
Mitochondria - metabolism
Mitochondrial dysfunction
Neurodegeneration
Neurodegenerative Diseases - enzymology
Neurodegenerative Diseases - pathology
Neurons - enzymology
Neurons - pathology
PARP-1
Parthanatos
PARylation
Poly(ADP-ribose) Polymerases - metabolism
Protein Interaction Maps
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Summary: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.
ISSN:1084-9521
1096-3634
DOI:10.1016/j.semcdb.2016.11.007