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Poly(ADP-ribose) drives pathologic α-synuclein neurodegeneration in Parkinson’s disease.


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
DOI: 10.1126/science.aat8407
PubMed publication date (edat): 11/6/2018

Abstract

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.
Comment in
* 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]

PMID: 30385548
Free Full-Text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6431793/

Maximus Peto

Max Peto is a longevity researcher and founder of Long Life Labs. A biochemist by training, he studies the biochemistry of aging and longevity and has worked with research organizations such as SENS Research Foundation, Methuselah Foundation, BioAge Labs, Life Extension Foundation, and Ichor Therapeutics. His work at Long Life Labs is focused on empowering people to understand and manage the most critical factors for better health and longer life.

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