Maximus Peto’s Commentary
I have corresponded with James Clement about the possibility that elevated PARP-1 activity may a primary cause of the decline of NAD+ during aging, because PARP-1 consumes NAD+ as a cofactor in its activity. This group reports that PARP-1 also apparently accelerates the formation of toxic alpha-synuclein, and in at least one model, PARP-1 inhibition or deletion could prevent alpha-synuclein toxicity. PARP-1 inhibition or deletion does not seem like an enduring solution, as it leaves us tinkering with metabolism instead of cleaning up damage. I do wonder why PARP-1 is upregulated during aging; perhaps if we address the cause of this upregulation, we could prevent these negative downstream effects.
Poly(ADP-ribose) drives pathologic α-synuclein neurodegeneration in Parkinson’s disease.
Science. 2018 Nov 2;362(6414). pii: eaat8407.
Kam TI et al
PubMed publication date (edat): 11/6/2018
The pathologic accumulation and aggregation of α-synuclein (α-syn) underlies Parkinson’s disease (PD). The molecular mechanisms by which pathologic α-syn causes neurodegeneration in PD are not known. Here, we found that pathologic α-syn activates poly(adenosine 5′-diphosphate-ribose) (PAR) polymerase-1 (PARP-1), and PAR generation accelerates the formation of pathologic α-syn, resulting in cell death via parthanatos. PARP inhibitors or genetic deletion of PARP-1 prevented pathologic α-syn toxicity. In a feed-forward loop, PAR converted pathologic α-syn to a more toxic strain. PAR levels were increased in the cerebrospinal fluid and brains of patients with PD, suggesting that PARP activation plays a role in PD pathogenesis. Thus, strategies aimed at inhibiting PARP-1 activation could hold promise as a disease-modifying therapy to prevent the loss of dopamine neurons in PD.
* Cancer enzyme affects Parkinson’s disease. [Science. 2018] * The Cell-Death-Associated Polymer PAR Feeds Forward α-Synuclein Toxicity in Parkinson’s Disease. [Mol Cell. 2019] * Parkinson’s disease: How do highly toxic α-Synuclein/PAR aggregates mediate neuronal cell death? [Mov Disord. 2019]
Free Full-Text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6431793/