An unSIRTain role in neurodegeneration

The family of proteins called sirtuins (named after the founding member, the yeast gene Silent Information Repressor-2) are intimately connected with the history of modern biogerontology. Originally identified as key players in the determination of yeast replicative lifespan, these proteins were subsequently shown to play essential roles in life-extension pathways in worms. More recent findings suggest that sirtuins are also important in regulation of mammalian aging — though the story there is more complex, with seven SIR2 homologs in the human and mouse genomes, each with its own tissue specificity and subcellular localizations.

Small-molecule sirtuin activators such as resveratrol have been shown to promote longevity in specific animal models (see our earlier articles, Resveratrol, lifespan and an unhealthy diet and Resveratrol: Breakfast of champions), raising the hope that such compounds could be developed as a means of therapeutically intervening in the natural aging process or as a prophylactic against age-related diseases (see Toward sirtuin activators in the clinic).

Where questions are asked about diseases of aging, the discussion will eventually turn toward the great scourge of age-related neurodegenerative disease. Given that sirtuins have already demonstrated potential to positively impact the aging process in a wide range of animals, it seems logical to ask whether they might also have therapeutic or prophylactic potential against neurodegeneration.

The answer may end up being murky, and rely on the specific details of the specific illness and sirtuin family member in question. Two recent papers have studied the effect of sirtuin expression (and pharmaceutical modulation of sirtuin activity) on neurodegenerative disease — and come up with two diametrically opposing answers.

The first study yielded result that one might expect, given the well-documented pro-longevity effects of sirtuins discussed above. Kim et al. showed that both overexpression of SIRT1 and administration of the activator resveratrol had a salutary effect in models of two kinds of neurodegeneration, Alzheimer’s disease (AD) and ALS:

SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer’s disease and amyotrophic lateral sclerosis

A progressive loss of neurons with age underlies a variety of debilitating neurological disorders, including Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS), yet few effective treatments are currently available. The SIR2 gene promotes longevity in a variety of organisms and may underlie the health benefits of caloric restriction, a diet that delays aging and neurodegeneration in mammals. Here, we report that a human homologue of SIR2, SIRT1, is upregulated in mouse models for AD, ALS and in primary neurons challenged with neurotoxic insults. In cell-based models for AD/tauopathies and ALS, SIRT1 and resveratrol, a SIRT1-activating molecule, both promote neuronal survival. In the inducible p25 transgenic mouse, a model of AD and tauopathies, resveratrol reduced neurodegeneration in the hippocampus, prevented learning impairment, and decreased the acetylation of the known SIRT1 substrates PGC-1alpha and p53. Furthermore, injection of SIRT1 lentivirus in the hippocampus of p25 transgenic mice conferred significant protection against neurodegeneration. Thus, SIRT1 constitutes a unique molecular link between aging and human neurodegenerative disorders and provides a promising avenue for therapeutic intervention.

In contrast, Outeiro et al. found that inhibition of another sirtuin, SIRT2, was neuroprotective in a model of Parkinson’s disease:

Sirtuin 2 Inhibitors Rescue alpha-Synuclein-Mediated Toxicity in Models of Parkinson’s Disease

The sirtuins are members of the histone deacetylase family of proteins that participate in a variety of cellular functions and play a role in aging. Here, we identified a potent inhibitor of sirtuin 2 (SIRT2), and found that inhibition of SIRT2 rescued alpha-synuclein toxicity and modified inclusion morphology in a cellular model of Parkinson’s disease. Genetic inhibition of SIRT2 via siRNA similarly rescued alpha-synuclein toxicity. Furthermore, the inhibitors protected against dopaminergic cell death both in vitro and in a Drosophila model of Parkinson’s disease. The results suggest a link between neurodegeneration and aging.

Why the dramatic difference in results? The answer could lie either in differences between the diseases studied or in the functions of the sirtuin family members that were targeted.

AD and Parkinson’s are both characterized by protein misfolding and amyloid aggregation of specific proteins (Aß and alpha-synuclein, respectively), but there are distinct differences at the cellular level: Aß plaques tend to be extensively deposited outside the cell, whereas alpha-synuclein inclusion bodies are almost entirely intracellular. Although both diseases result in neuronal cell death, they affect cells in different parts of the brain, and consequently have very different clinical presentations and symptomatology. My expertise in the specifics of neurodegenerative disease is rather limited, so I’ll close this thought by merely pointing out the formal possibility that despite some superficial similarities in cellular etiology, idiosyncrasies of AD or Parkinson’s might be sufficient to explain the seemingly contradictory findings.

It is also possible that SIRT1 (expressed/activated in the AD paper) and SIRT2 (inhibited in the Parkinson’s paper) have very different biochemical functions, and that this difference explains their opposing influences on neurodegeneration. We already know from the work of Matt Kaeberlein and colleagues that resveratrol potently stimulates SIRT1 but not SIRT2, suggesting that despite their homology and conserved deacetylase activities, these proteins differ substantially in molecular detail. We also know that the preferred substrates of the two proteins differ: SIRT1 acts primarily on histones, and thereby influences chromatin state and transcription; in contrast, SIRT2 targets tubulin and appears to play a role in the control of differentiation and mitosis.

It is therefore tempting to speculate that SIRT1 activity either triggers expression of neuroprotective genes or represses genes actively involved in cell death; stimulation of this protein, either by ectopic overexpression or the administration of an activator, would delay the progress of Alzheimer’s pathology. In contrast, SIRT2 lacks the gene-regulatory activity of SIRT1, and thus inhibiting it should have no preventive effect on cell death.

It remains a mystery how tubulin acetylation might influence the life-or-death outcome of protein aggregation in neurons. Certainly, tubulin is an essential component of the complex neuronal cytoskeleton and the transport machinery that delivers critical materials back and forth along the axons and dendrites. Hence, it’s not too much of a stretch to imagine that alterations in tubulin acetylation could dramatically impact a cell already under stress due to protein aggregation toxicity.

Taken together, these two studies underscore the importance of understanding the detailed molecular mechanism of drug action. While resveratrol appears to be selective for SIRT1 vs SIRT2, it is not necessary for all chemical modulators of sirtuin activity to observe the same preference. A hypothetical broad-spectrum sirtuin activator might end up doing more harm than good — regardless of its pharmacokinetics, bioavailability, or for that matter patentability/profitability — if it delayed Alzheimer’s (via SIRT1) only to speed the progress of Parkinson’s (via SIRT2). As we develop more compounds to target sirtuins, then, it will be critical not only to monitor efficacy in limited contexts, but also to carefully enumerate off-target effects on proteins within the same family.


One comment

  1. Very informative post.

    I also noticed the somewhat conflicting results of the two papers regarding sirt1 and sirt2. Thanks for your analysis.

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