Researchers at the University of Cambridge have published an interesting research report last week regarding a clinically available drug that they suggest boosts autophagy in the brain.
Autophagy is one of several processes that cells use to dispose of waste and old proteins.
The drug is called Felodipine, and it is a calcium channel blocker that is used to treat high blood pressure.
In today’s post, we will look at what autophagy is, how boosting it could help with neurodegenerative conditions, and whether Felodipine should be clinically tested for re-purposing to Parkinson’s.
Prof Rubinsztein is the Deputy Director of the CIMR, the Academic Lead of the UK Alzheimer’s Research UK Cambridge Drug Discovery Institute, and he is a group leader at the UK Dementia Research Institute at the University of Cambridge.
He is also one of the world’s leading experts in the field of autophagy in neurodegenerative conditions.
What is autophagy?
Alpha synuclein is a protein that is closely associated with Parkinson’s. But exactly if and how it is connected to the neurodegenerative process underlying the condition, remains unclear.
Last week researchers reported that removing a particular form of alpha synuclein in mice results in a very early onset appearance of characteristics that closely resemble the features of Parkinson’s that we observe in humans. This finding has caused some excitement in the research community, as not only does this tell us more about the alpha synuclein protein, but it may also provide us with a useful, more disease-relevant mouse model for testing therapies.
In today’s post, we will discuss what alpha synuclein is, explain which form of the protein was disrupted in this mouse model, review the results of the new study, and look at how tetramer stablising drugs could be a new area of PD therapeutics.
The 337 metre (1,106 ft) long USS Gerald R. Ford. Source: Wikipedia
Imagine you and I are standing in front of the world’s largest aircraft carrier, the USS Gerald R. Ford.
It is a VAST warship – measuring in at 337 metres (1,106 ft) in length, 76 metres (250 feet) in height – and it is a wonder of engineering composed of over a billion individual components.
And as we are standing there, gazing up at this amazing machine, I turn to you and put a nut & bolt into the palm of your hand.
A nut and bolt. Source: Atechleader
You look down at it for a moment, then turn to me, puzzled.
And that is when I say: “I would like you to find (without aid/instructions) where on this ship versions of this particular type of nut and bolt live, and try to determine exactly what functions they have“.
Where would you even start?
What tools would you use for the job? Considering the size and complexity of the vessel, would you simply give up before even starting?
It sounds like a ridiculously daunting task, but this is in effect what neurobiologists are trying to do with their study of the brain. They start with a protein – one of the functional pieces of machinery inside each cell of our body – and then try to determine where in the brain it lives (the easy part) and what it does exactly (the REALLY hard part – most proteins have multiple functions and different configurations).
A good example of this is the Parkinson’s-associated protein alpha synuclein:
Alpha synuclein. Source: Wikipedia
Alpha synuclein is one of the most abundant proteins in our brains – making up about 1% of all the proteins floating around in each neuron in your head – and it is a very well studied protein (with over 9700 research reports listed on the Pubmed search engine with the key words ‘alpha synuclein’).
But here’s the thing: we are not entirely clear on what alpha synuclein actually does inside the cell.
In fact, biologists are not even sure about what the ‘native’ form of alpha synuclein is!
What do you mean?
Aspirin is one of the oldest drugs in medical use today.
Recently researchers noticed something interesting about ‘low doses’ of aspirin that could have implications for Parkinson’s: It raises the amount of dopamine in the brain
Specifically, low doses of aspirin triggers an increase in the levels of an enzyme called tyrosine hydroxylase, which is involved in the production of chemical dopamine. Given that levels of dopamine are severely reduced in the brain of a person with Parkinson’s, this new result is kind of interesting.
In today’s post, we will have a look at what aspirin and tyrosine hydroxylase are, what the new research results report, and what this could mean for the Parkinson’s community.
The Ebers Papyrus (also known as the also known as Papyrus Ebers) is considered one of the most oldest medicinal “encyclopedias”.
It outlines 700 Egyptian medicinal formulas and remedies dating back to circa 1550 BC. We know nothing about who wrote the document (even the source of the papyrus is unknown – it may have been found with a mummy in the El-Assasif district of the Theban necropolis).
One thing is clear though: the people who wrote it were a very far sighted bunch.
Interestingly, the papyrus mentions use of Willow bark and Myrtle to treat fever and pain. Both of these plants are rich in Salicylic acid.
What is Salicylic acid?
It is an active precursor (or metabolite) of acetylsalicylic acid – which is also known as ‘Aspirin’.
What exactly is aspirin?
Nuclear factor erythroid 2–related factor 2 (or NRF2) is a protein in each of your cells that plays a major role in regulating resistance to stress. As a result of this function, NRF2 is also the target of a lot of research focused on neuroprotection.
A group of researchers from the University of British Columbia have recently published interesting findings that point towards to a biological pathway that could help us to better harness the beneficial effects of NRF2 in Parkinson’s.
In today’s post, we will discuss what NRF2 is, what the new research suggests, and how we could potentially make use of this new information.
Rusting iron. Source: Thoughtco
In his book ‘
xidation nibbles more slowly – more delicately, like a tortoise – at the world around us, without a flame, we call it rust and we sometimes scarcely notice as it goes about its business consuming everything from hairpins to whole civilizations”
And he was right on the money.
Oxidation is the loss of electrons from a molecule, which in turn destabilises that particular molecule. It is a process that is going on all around us – even within us.
Iron rusting is the example that is usually used to explain oxidation. Rust is the oxidation of iron – in the presence of oxygen and water, iron molecules will lose electrons over time. And given enough time, this results in the complete break down of objects made of iron.
The combustion process of fire is another example, albeit a very rapid form of oxidation.
Oxidation is one half of a process called Redox – the other half being reduction (which involves the gaining of electrons).
The redox process. Source: Academic
Here is a video that explains the redox process:
Now it is important to understand, that oxidation also occurs in biology.
Molecules in your body go through the same process of losing electrons and becoming unstable. This chemical reaction leads to the production of what we call free radicals, which can then go on to damage cells.
What is a free radical?
In this post we discuss several recently published research reports suggesting that Parkinson’s disease may be an autoimmune condition. “Autoimmunity” occurs when the defence system of the body starts attacks the body itself.
This new research does not explain what causes of Parkinson’s disease, but it could explain why certain brain cells are being lost in some people with Parkinson’s disease. And such information could point us towards novel therapeutic strategies.
The first issue of Nature. Source: SimpleWikipedia
The journal Nature was first published on 4th November 1869, by Alexander MacMillan. It hoped to “provide cultivated readers with an accessible forum for reading about advances in scientific knowledge.” It has subsequently become one of the most prestigious scientific journals in the world, with an online readership of approximately 3 million unique readers per month (almost as much as we have here at the SoPD).
Each Wednesday afternoon, researchers around the world await the weekly outpouring of new research from Nature. And this week a research report was published in Nature that could be big for the world of Parkinson’s disease. Really big!
On the 21st June, this report was published:
Title: T cells from patients with Parkinson’s disease recognize α-synuclein peptides
Authors: Sulzer D, Alcalay RN, Garretti F, Cote L, Kanter E, Agin-Liebes J, Liong C, McMurtrey C, Hildebrand WH, Mao X, Dawson VL, Dawson TM, Oseroff C, Pham J, Sidney J, Dillon MB, Carpenter C, Weiskopf D, Phillips E, Mallal S, Peters B, Frazier A, Lindestam Arlehamn CS, Sette A
Journal: Nature. 2017 Jun 21. doi: 10.1038/nature22815.
In their study, the investigators collected blood samples from 67 people with Parkinson’s disease and from 36 healthy patients (which were used as control samples). They then exposed the blood samples to fragments of proteins found in brain cells, including fragments of alpha synuclein – this is the protein that is so closely associated with Parkinson’s disease (it makes regular appearances on this blog).
What happened next was rather startling: the blood from the Parkinson’s patients had a strong reaction to two specific fragments of alpha synuclein, while the blood from the control subjects hardly reacted at all to these fragments.
In the image below, you will see the fragments listed along the bottom of the graph (protein fragments are labelled with combinations of alphabetical letters). The grey band on the plot indicates the two fragments that elicited a strong reaction from the blood cells – note the number of black dots (indicating PD samples) within the band, compared to the number of white dots (control samples). The numbers on the left side of the graph indicate the number of reacting cells per 100,000 blood cells.
The investigators concluded from this experiment that these alpha synuclein fragments may be acting as antigenic epitopes, which would drive immune responses in people with Parkinson’s disease and they decided to investigate this further.