Mitochondrial Metabolism Regulates Microtubule Acetylome and Autophagy Trough Sirtuin-2: Impact for Parkinson’s Disease

Abstract

Alterations in microtubule-dependent transport, mitochondrial dysfunction, and autophagic pathology are involved in neurodegeneration observed in sporadic Parkinson's disease. However, the mechanistic link connecting these events remains elusive. We observed that NAD metabolism is altered in sporadic Parkinson's disease patient-derived cells, which contributes to Sirtuin-2 activation and subsequent decrease in acetylated-α-tubulin levels. Pharmacological inhibition of sirtuin-2 deacetylase activity selectively enhanced α-tubulin acetylation and facilitated the trafficking and clearance of misfolded proteins. Sirtuin-2 knock-out mice neurons had no alteration in microtubule assembly after exposure to MPP, allowing the maintenance of a normal autophagic flux. These data were validated using MPTP-treated sirtuin-2 knock-out mice, where no alterations in motor behavior were observed. Biochemical analysis of sporadic Parkinson's disease patient brains supports the in vitro and in vivo data. Our data provide strong evidence that sirtuin-2 controls the functional ability of the autophagic system through acetylation and highlight the association between mitochondrial metabolism and neurodegeneration in sporadic Parkinson's disease.

Decreased Sirtuin Deacetylase Activity in LRRK2 G2019S iPSC-Derived Dopaminergic Neurons

“…However, our data suggest that the altered mitochondrial trafficking may be independent of mutant LRRK2 as neither LRRK2 G2019S-expressing glutamatergic neurons nor sensory neurons exhibit altered mitochondrial trafficking, and the LRRK2 kinase inhibitor GSK2578215A did not improve trafficking defects in dopaminergic neurons. It is important to note that our data are in contrast to a recent report showing that NAD + levels and SIRT2 deacetylase activity were increased in PD patient-derived cybrid cell lines ( Esteves et al., 2017 ). This discrepancy could be due to differences between the cybrid and iPSC model systems, but another plausible explanation could be due to variations in NAD + levels among different cell types, as demonstrated by the variable levels in dopaminergic, glutamatergic, and sensory neurons.…”

Emerging Role of Sirtuin 2 in Parkinson’s Disease

“…In animal models of PD, MPP + specifically acts on the kinetic system of MT synthesis, thereby impairing this process and promoting apoptosis of DA neurons, confirming the importance of a functioning MT in the context of PD (Cappelletti et al, 2005). In sporadic PD patient-derived cells, it was observed that selective inhibition of SIRT2 restored the levels of tubulin acetylation, reducing the ratio of free/polymerized tubulin and improving MT-mediated transportation (Esteves et al, 2018). In addition, AK7-mediated inhibition of SIRT2 results in increased levels of acetylated α-tubulin, attenuating the loss of striatal DA and nigral TH + neurons and improving motor function.…”

“…This modification is also associated with other biological processes such as fibrillar hair depolymerization, cell migration, and autophagy, and is known to influence cellular stress, inflammation and viral responses (Ishiguro et al, 2011;Misawa et al, 2013;Sabo et al, 2013;Mackeh et al, 2014;Wang et al, 2014). In sporadic PD brains, a decrease in the level of acetylated MT could be caused by a change in mitochondrial metabolism, which is related to the activation of SIRT2 (Esteves et al, 2018).…”

Astragaloside-IV Alleviates Heat-Induced Inflammation by Inhibiting Endoplasmic Reticulum Stress and Autophagy

“…It is activated by extracellular or intracellular stress such as starvation, heat, infection, and ER stress. There is some evidence that ER stress-induced autophagy can also keep cells from oxidants, ATP depletion, and IR injury by eliminating damaged organelles and protein aggregates formed during the injury [30, 31]. However, in some conditions, excessive autophagy caused by stress may exceed the cell-bearing capacity and lead to inflammation, apoptosis, and cell death.…”