Comparison of Sirtuin 3 Levels in ALS and Huntington’s Disease—Differential Effects in Human Tissue Samples vs. Transgenic Mouse Models

Abstract

Neurodegenerative diseases are characterized by distinct patterns of neuronal loss. In amyotrophic lateral sclerosis (ALS) upper and lower motoneurons degenerate whereas in Huntington’s disease (HD) medium spiny neurons in the striatum are preferentially affected. Despite these differences the pathophysiological mechanisms and risk factors are remarkably similar. In addition, non-neuronal features, such as weight loss implicate a dysregulation in energy metabolism. Mammalian sirtuins, especially the mitochondrial NAD+ dependent sirtuin 3 (SIRT3), regulate mitochondrial function and aging processes. SIRT3 expression depends on the activity of the metabolic master regulator peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), a modifier of ALS and HD in patients and model organisms. This prompted us to systematically probe Sirt3 mRNA and protein levels in mouse models of ALS and HD and to correlate these with patient tissue levels. We found a selective reduction of Sirt3 mRNA levels and function in the cervical spinal cord of end-stage ALS mice (superoxide dismutase 1, SOD1G93A). In sharp contrast, a tendency to increased Sirt3 mRNA levels was found in the striatum in HD mice (R6/2). Cultured primary neurons express the highest levels of Sirt3 mRNA. In primary cells from PGC-1α knock-out (KO) mice the Sirt3 mRNA levels were highest in astrocytes. In human post mortem tissue increased mRNA and protein levels of Sirt3 were found in the spinal cord in ALS, while Sirt3 levels were unchanged in the human HD striatum. Based on these findings we conclude that SIRT3 mediates the different effects of PGC-1α during the course of transgenic (tg) ALS and HD and in the human conditions only partial aspects Sirt3 dysregulation manifest.

SIRT3 activator honokiol ameliorates surgery/anesthesia‐induced cognitive decline in mice through anti‐oxidative stress and anti‐inflammatory in hippocampus

“…SIRT3 is the one member of the sirtuin family that exhibits deacetylase activity and is mainly localized to the mitochondria. Regarding to oxidative stress, SIRT3 mainly regulates mitochondrial ROS levels by deacetylating SOD2 and has a positive role in several neurological disorders, including AD, PD and Huntington's disease . And with the downregulated of oxidative stress, the inflammatory and related cytokines can also be normalized.…”

“…Regarding to oxidative stress, SIRT3 mainly regulates mitochondrial ROS levels by deacetylating SOD2 and has a positive role in several neurological disorders, including AD, PD and Huntington's disease. [53][54][55][56] And with the downregulated of oxidative stress, the inflammatory and related cytokines can also be normalized. Second, in current studies, our just tested the surgery/anesthesiainduced neuroinflammatory and oxidative stress in hippocampus of mice, but other region in brain (such as prefrontal cortex) and systemic inflammation was not investigated.…”

Signaling and Regulation Through the NAD+and NADP+Networks

“…In postmortem CNS samples from ALS and HD patients the PGC-1 and SIRT3 levels shift to opposite directions: In human ALS spinal cords the SIRT3 content increases, but in HD cerebellum and striatum the levels are not different from controls. In summary, the PGC-1 and SIRT3 changes are small, and the published data do not lend solid support to a hypothesis of SIRT3 involvement in the pathogenesis of ALS or HD (13).…”

Antioxidant Alternatives in the Treatment of Amyotrophic Lateral Sclerosis: A Comprehensive Review

“…Sirtuin 3 (SIRT3) regulates mitochondrial function and the aging processes (Buck et al, 2017) by activating SOD2 and CAT (Salvatori et al, 2017) that are involved in the detoxification of ROS (Qiu et al, 2010;Kida and Goligorsky, 2016) (Figure 2).…”