SIRT1: A Piece of the Parkinson’s Puzzle

A neuroscience blog such as ours would be remiss not to discuss Parkinson’s Disease, the second most common neurodegenerative disorder after Alzheimer’s. Parkinson’s Disease (PD) is characterized by the loss of dopaminergic neurons, accumulation of phosphor-α-synuclein, and the presence of Lewy bodies [1]. The exact causes of PD, like many other progressive neurodegenerative disorders, are still unknown, but oxidative stress (the imbalance of free radical production and antioxidant defenses) is suggested to play a role in neurodegeneration progression [1]. Recent discoveries discussed in a paper by Singh et. al have indicated that the protein SIRT1 has the ability to help reduce cell damage caused by oxidative stress, so today’s blog post will discuss some of the findings of this paper, and how they relate to Parkinson’s Disease.

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Figure 1: A flowchart of the SIRT 1 pathway. [Image Link]
Sirtuin 1 (SIRT1) is a protein localized to the nucleus that promotes proteins involved in DNA repair, antioxidant defense, and apoptosis. SIRT1 slows aging, reduces oxidative stress, and ultimately increases cell survivability [1]. Figure 1 on the right shows how SIRT1 can deacetylate (reduce gene expression of) various factors, some of which will be discussed in more detail below.

 

A recent paper by Singh et. al investigated this possible protective role of SIRT1 in neurodegeneration, and found that it not only reduced damage caused by oxidative stress in cells, but was also down-regulated in PD patients. In other words, patients with PD or PD dementia had very low levels of SIRT1, indicating that SIRT1 might be involved in a pathway related to PD neurodegeneration.  To test its potential neuroprotective role, the authors over-expressed SIRT1 in SH-SY5Y cells and treated them with either diquat or rotenone, two toxins that have been known to cause oxidative damage in dopaminergic neurons [1].

Screen Shot 2017-11-15 at 3.00.04 PMThis figure from Singh et. al’s paper shows the differences in cell viability between the two treatments. SH-SY5Y cells were transfected with either SIRT1, catalytically inactive SIRT1H363Y, or an empty pLenti CMV plasmid. The researchers then probed for NF-κB, a protein complex that is induced by oxidative stress. They found reduced expression of NF-κB in cells with SIRT1 over-expression, indicating that SIRT1 promotes cell survivability.  SIRT1WT cells had a 55% reduction of NF-κB levels after rotenone treatment, and a 50-55% reduction of NF-κB after diquat treatment compared to the controls. After treatment of either diquat and rotenone, SIRT1 transfected cells showed enhanced cell viability, suggesting that SIRT1 suppresses NF-κB and indeed has a protective role when cells are under toxin-induced oxidative stress. [1]

Here comes my favorite part: fluorescent immunocytochemistry! The colorful images you see below not only make super cool desktop wallpapers reminiscent of our childhood lava lamps, but they also illustrate the significant reduction in accumulation of phosphor-α-synuclein staining in SIRT1 transfected cells as opposed to the cells with empty control plasmids. Oligomerisation and aggregation of phosphor-α- synuclein protein is triggered by oxidative stress, and results in the formation of the Lewy bodies characteristic of PD. [1] Phosphor-α- synuclein is the main protein component of Lewy bodies, and its self-propagating nature has made it a notoriously large contributor to PD pathogenesis [2]. In the image above, we can see that SIRT1-transfected cells treated with toxin had significantly less phosphor-α-synuclein aggregates as opposed to their control plasmid counterparts, illustrating the protective role of SIRT1 in reducing damage caused oxidative stress, and by extension, neurodegeneration.

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There are some caveats. Joseph Cohen, author of the popular Selfhacked blog did a great job summarizing some of the negative effects SIRT1 can have: Firstly, SIRT1’s effects are tissue dependent [3], so the protective effects we see in some tissues may not be observed in other tissues. High levels of SIRT1 are also known to decrease pancreatic beta cell production, causing reductions in insulin production that could contribute to diabetes [3]. Lastly, p53, a tumor-suppressing protein is also deacetylated by SIRT1, as shown in Figure 1 above, preventing p53 from initiating apoptosis in potentially cancerous cells [3].

So, just because we saw that Parkinson’s patients happened to have down-regulation of SIRT1, we can’t necessarily just up-regulate SIRT1 and expect that it will fix all our problems. SIRT1 may be useful in developing treatments, but it is only part of the big picture since as a standalone, it also has its own harmful effects when over-expressed.  Unfortunately, some of the negative effects of SIRT1, such as deacetylation of p53, are on-target effects, so they will be difficult to avoid (as opposed to off-target/side effects). These negative effects of SIRT1, in addition to others, are why treating/curing neurodegenerative diseases is truly such a puzzle; however, we can’t deny that some of SIRT1’s effects will absolutely be useful if they can be harnessed into a treatment.

Parkinson’s Disease is one of the “big ones” in terms of neurodegenerative disorders. Singh et. al made some important discoveries about SIRT1 that gives researchers a great clue about where treatment developments should start. Though I am just a lowly undergrad who is but a neophyte in the world of research, I found the data in this paper to be very convincing in terms of SIRT1’s potential in neurodegenerative disorder treatment. There are, of course, some downsides to over-expression of SIRT1 exclusively, but I think it will definitely play a big role in the mechanism for treatments that are developed. I’m very excited about SIRT1’s potential, and I can’t wait to see how this data is used moving forward in helping patients with Parkinson’s, Alzheimer’s, and other progressive neurodegenerative disorders.

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References:

1. Singh, Preeti, Peter S. Hanson, and Christopher M. Morris. “SIRT1 Ameliorates Oxidative Stress Induced Neural Cell Death and Is down-Regulated in Parkinson’s Disease.” BMC Neuroscience 18 (2017): 46. PMC. Web. 17 Nov. 2017.

2. Recasens, Ariadna, and Benjamin Dehay. “Alpha-Synuclein Spreading in Parkinson’s Disease.” Frontiers in Neuroanatomy 8 (2014): 159. PMC. Web. 17 Nov. 2017.

3. Cohen, Joseph M. “SIRT1: Its Role In Chronic Health Issues and How to Increase and Decrease It.” Selfhacked, 30 Oct. 2017.

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