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NR Alleviates a Fly Model of a Common Contributor to Parkinson's

nicotinamide riboside parkinsons disease

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#1 Michael

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Posted 07 June 2018 - 03:42 PM


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Schöndorf DC, Ivanyuk D, Baden P, Sanchez-Martinez A, De Cicco S, Yu C, Giunta I, Schwarz LK, Di Napoli G, Panagiotakopoulou V, Nestel S, Keatinge M, Pruszak J, Bandmann O, Heimrich B, Gasser T, Whitworth AJ, Deleidi M.

The NAD+ Precursor Nicotinamide Riboside Rescues Mitochondrial Defects and Neuronal Loss in iPSC and Fly Models of Parkinson's Disease. Cell Rep. 2018 Jun 5;23(10):2976-2988. doi: 10.1016/j.celrep.2018.05.009. PubMed PMID: 29874584.
 
... genetic and biochemical studies now indicate that mitochondrial dysfunction and cellular energy failure are key to PD ... However, it is still unclear whether mitochondrial defects are actual disease drivers and increasing mitochondrial biogenesis provides neuroprotection in PD. In addition, little is known about NAD+ metabolism and availability of NAD+ precursors in human neurons.
 
Here, we have addressed these fundamental questions in an induced pluripotent stem cell (iPSC) neuronal model of PD bearing mutations in the lysosomal enzyme β-Glucocerebrosidase (GBA) gene (GBA-PD), the most common genetic risk for PD ... GCase is a lysosomal enzyme that catalyzes the hydrolysis of glucosylceramide (GlcCer), a membrane glycosphingolipid, to ceramide and glucose, and both loss and gain of its enzymatic function may contribute to disease. According to the loss-of-function hypothesis, GCase deficiency causes substrate accumulation that alters lysosomal function and promotes α-synuclein aggregation ... β-Glucocerebrosidase (GCase) activity is reduced not only in mutation carriers but also in idiopathic PD and healthy individuals at older age (Gegg et al., 2012, Rocha et al., 2015), pointing toward a general role for GCase in brain aging and neurodegenerative processes. Importantly, patients with GBA mutations represent an etiologically homogeneous subgroup of PD, therefore providing the ideal cohort for precision medicine approaches.The pathogenetic mechanisms involved in GBA-PD are only partially understood and include autophagic defects, increased α-synuclein aggregation, calcium dyshomeostasis, and endoplasmic reticulum (ER) stress (Migdalska-Richards and Schapira, 2016). ...

 

We address these questions using patient-derived induced pluripotent stem cells and Drosophila models of GBA-related PD (GBA-PD), the most common PD genetic risk. Patient neurons display stress responses, mitochondrial demise, and changes in NAD+ metabolism. NAD+ precursors have been proposed to ameliorate age-related metabolic decline and disease. We report that increasing NAD+ via the NAD+ precursor nicotinamide riboside (NR) significantly ameliorates mitochondrial function in patient neurons. Human neurons require nicotinamide phosphoribosyltransferase (NAMPT) to maintain the NAD+ pool and utilize NRK1 to synthesize NAD+ from NAD+ precursors. Remarkably, NR prevents the age-related dopaminergic neuronal loss and motor decline in fly models of GBA-PD.

 

This is very preliminary — I don't take fly models of neurodegenerative disease very seriously, and they have limited results in patient-derived iPSC — but this does look like it has potential.

 

It also bears noting that "garden variety" nicotinamide has also been found beneficial in other (fly) models of rarer, more purely genetic forms of PD:

https://www.ncbi.nlm...les/PMC5312101/
https://www.nature.c...les/cddis201672


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#2 stefan_001

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Posted 09 June 2018 - 04:25 PM

I think its interesting that they found markers indicating mitophagy went up.







Also tagged with one or more of these keywords: nicotinamide riboside, parkinsons disease

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