Tagged: Pink

NIX-ing the PARKIN and PINK1 problem

In American slang, to ‘nix‘ something is to ‘put an end to it’.

Curiously, a protein called NIX may be about to help us put an end to Parkinson’s disease, at least in people with specific genetic mutations.

In today’s post we will look at what NIX is, outline a new discovery about it, and discuss what this new information will mean for people living with Parkinson’s disease.


Sydney harbour. Source: uk.Sydney

Before we start, I would like the reader to appreciate that I am putting trans-Tasman rivalry side here to acknowledge some really interesting research that is being conducted in Australia at the moment.

And this is really interesting.

I have previously spoken a lot about mitochondria and Parkinson’s on this website. For the uninitiated, mitochondria are the power house of each cell. They help to keep the lights on. Without them, the party is over and the cell dies.

Mitochondria

Mitochondria and their location in the cell. Source: NCBI

You may remember from high school biology class that mitochondria are tiny bean-shaped objects within the cell. They convert nutrients from food into Adenosine Triphosphate (or ATP). ATP is the fuel which cells run on. Given their critical role in energy supply, mitochondria are plentiful (some cells have thousands) and highly organised within the cell, being moved around to wherever they are needed.

Like you and I and all other things in life, however, mitochondria have a use-by date.

As mitochondria get old and worn out (or damaged) with time, the cell will recycle them via a process called mitophagy (a blending of the words mitochondria and autophagy – the waste disposal system of each cell).

What does this have to do with Parkinson’s disease?

Well, about 10% of Parkinson’s cases are associated with particular genetic variations that render people vulnerable to developing the condition. Some of these mutations are in sections of DNA (called genes) that provide the instructions for proteins that are involved in the process of mitophagy. Two genes, in particular, are the focus of a lot of Parkinson’s-related research – they are called PARKIN and PINK1.

What do PARKIN and PINK1 do?

Continue reading

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The autoimmunity of Parkinson’s disease?

Auto

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.


Nature_cover,_November_4,_1869

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:

Nature
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.
PMID: 28636593

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.

Table1

Source: Nature

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.

Continue reading

Pink flies in Leicester at it again

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Imagine discovering a protein that could make the power supply of your cells healthier AND perhaps provide a new therapeutic target for Parkinson’s disease.

That would be a pretty big deal right?

Well, this week, researchers may have found just such a protein. In today’s post we will review their finding and discuss what it means for Parkinson’s disease.


This is Dr Miguel Martins:

miguel_martins

Source: Tox.mrc.ac.uk

He’s a dude.

Dr Martins is a group leader at the MRC toxicology unit in Leicester – a city in the East Midlands of England.

leicester-town-hall-squareLeicester. Source: Keithvazmp

You may have heard of Leicester. Last year their football team had a dream season, miraculously winning the Premier league title despite starting with odds of 5000:1.

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Last season’s winners. Source: Goal.com

This season, however,….well, uh…

Let’s move on, shall we.

Recently we reviewed Dr Martins research group’s work on ‘Pink flies’ and how they survive longer on Niacin rich diets (Click here for that post). He and his group were again publishing research this week, involving new a new study highlighting a protein that may help with keeping mitochondria healthy.

What are mitochondria?

Good question.

Mitochondria are the power house of each cell. They keep the lights on. Without them, the lights go out and the cell dies.

Mitochondria

Mitochondria and their location in the cell. Source: NCBI

You may remember from high school biology class that mitochondria are bean-shaped objects within the cell. They convert energy from food into Adenosine Triphosphate (or ATP). ATP is the fuel which cells run on. Given their critical role in energy supply, mitochondria are plentiful and highly organised within the cell, being moved around to wherever they are needed.

So what has Dr Martins group found?

This week they published this study:

atf4

Title: dATF4 regulation of mitochondrial folate-mediated one-carbon metabolism is neuroprotective.
Authors: Celardo I, Lehmann S, Costa AC, Loh SH, Miguel Martins L.
Journal: Cell Death Differ. 2017 Feb 17. [Epub ahead of print]
PMID: 28211874       (This article is OPEN ACCESS if you would like to read it)

In the study, the researchers were interested in determining what changes occur in the flies that are missing the Parkinson’s disease associated genes PINK1 or PARKIN, particularly which transcription factors are affected.

What is a transcription factor?

Another good question.

Ok, so you remember your high school science class when the adult at the front of the class was explaining biology 101? And they were saying that DNA gives rise to RNA, RNA gives rise to protein? The central dogma of biology. Remember this?

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The basic of biology. Source: Youtube

Ultimately this DNA-RNA-Protein mechanism is a circular cycle, because the protein that is produced using RNA is required at all levels of this process. Some of the protein is required for making RNA from DNA, while other proteins are required for making protein from the RNA instructions.

A transcription factor is a protein that is involved in the process of converting (or transcribing) DNA into RNA.

Importantly, a transcription factor can be an ‘activator’ of transcription – that is initiating or helping the process of generating RNA from DNA.

6567f50d30ad3ac65aff1e815caf202b3abd7111

An example of a transcriptional activator. Source: Khan Academy

Or it can be a repressor of transcription – blocking the machinery (required for generating RNA) from doing it’s work.

6286f2dbd5e353145bef785aecb273d25176ff23

An example of a transcriptional repressor. Source: Khan Academy

In their study, Dr Martins and colleagues were looking for changes in the levels of proteins that either initiate or repress transcription, as these are the proteins that are ultimately at the start of the process of making things happen.

And what do Parkin and Pink1 actually do?

About 10% of cases of Parkinson’s disease can be attributed to genetic mutations in particular genes. PINK1 and PARKIN are two of those genes.

People with particular mutations in the PINK1 or PARKIN gene are vulnerable to developing an early onset form of Parkinson’s disease.

As to what the protein that is generated from PINK1 or PARKIN DNA & RNA, well in normal, healthy cells, the PINK1 protein is absorbed by mitochondria and eventually degraded. In unhealthy cells, however, this process is inhibited and PINK1 starts to accumulate on the outer surface of the mitochondria. There, it starts grabbing the PARKIN protein. This pairing is a signal to the cell that this particular mitochondria is not healthy and needs to be removed.

601587-fig-003

Pink1 and Parkin in normal (right) and unhealthy (left) situations. Source: Hindawi

The process by which mitochondria are removed is called autophagy. Autophagy is an absolutely essential function in a cell. Without it, old proteins will pile up making the cell sick and eventually it dies. Through the process of autophagy, the cell can break down the old protein, clearing the way for fresh new proteins to do their job.

Think of autophagy as the waste disposal process of the cell.

In the absence of PINK1 and PARKIN – as is the case in some people with Parkinson’s disease who have genetic mutations in these genes – we believe that sick/damaged mitochondria start to pile up and are not disposed of appropriately. This results in the cell dying.

Ok, so the researchers were looking for transcription factors that change in the absence of PINK1 and PARKIN. How did they do this experiment?

They used flies.

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PINK flies. Source: Wallpapersinhq

The researchers took the heads (yes, I know, delightful stuff) of ‘young’ 3-day-old Pink1 and Parkin mutant flies and compared them to ‘aged’ heads from 21- and 30-day-old Parkin and Pink1 mutant flies, respectively. The comparison was specifically looking at transcription factors that change over time.

This analysis revealed a protein called activating transcription factor 4 (or ATF4).

The researchers found that ATF4 levels were higher in both Pink1 and Parkin mutants than levels in control flies. Importantly, the researchers next looked at the genes that this transcription factor (ATF4) was regulating, and they found that ATF4 was encouraging the production of proteins that protect mitochondria. The researchers noticed that when they reduced ATF4 in flies, the levels of these critical mitochondrial proteins dropped as well.

When the researchers reduced the levels of each of these critical mitochondrial proteins in flies, it resulted in impaired climbing ability (suggesting a locomotor deficit) and decreased lifespan. Interestingly, these protective mitochondrial proteins are increased in the Pink1 and Parkin flies, suggesting that efforts to keep the mitochondria healthy are active inside the cells.

Finally, the researchers increased the levels of these protective mitochondrial proteins in the Pink1 and Parkin mutants and they found that the mitochondrial function was improved, and neuronal cell loss was avoided. They concluded that their findings demonstrate a central role for ATF4 signalling in Parkinson’s disease and that this protein may represent a target for new therapeutic strategy.

So what does it all mean?

The researchers behind this study were looking for biological pathways that are altered in genetic forms of Parkinson’s disease and they have identified a protein that is involved with keeping mitochondria healthy. This pathway could represent a new therapeutic target for future treatments, and also opens a new door in our understanding of Parkinson’s disease.

ATF4 is currently not directly targeted by any medications (that we are aware of), but there are drugs in clinical trials that target proteins that subsequently activate ATF4. For example, Oncoceutics Inc. have a drug candidate called ONC201 (currently in phase II trials for brain cancer) which kills solid tumor cells by triggering an stress response which is dependent on ATF4 activation.

moa-diagram-5-31-16

Source: Oncoceutics Inc

We are not for a second suggesting that this is a viable drug for Parkinson’s disease (so PLEASE DON’T rush out and besiege the company for all of their stocks!) – ATF4 should be considered a very experimental target until these results are replicated by independent research groups. We are mentioning ONC201 here simply to indicate that there is a field of research surrounding this potential target (ATF4) and it may be worthwhile for the Parkinson’s community to follow up this line of investigation.

We are assuming that while Leicester football club is struggling, the Martins lab are currently investigating compounds that activate ATF4 (and the other critical mitochondrial proteins), and we will report any follow up work as it comes to hand.

Watch this space.


And if nothing we’ve written here makes any sense, the good folks at Leicester University have kindly provided a short video explaining the research:


Postscript (March 2017):

matters_journal

The Martins lab have done it again!

This time in the OPEN ACCESS online journal Science Matters, they have published this article:

Matters

Title: Folinic acid is neuroprotective in a fly model of Parkinson’s disease associated with pink1 mutations
Authors: Lehmann S , Jardine J, Garrido – Maraver J, Loh SH, & Martins LM
Journal: Science Matters

In this study, the researchers demonstrated that a folinic acid-enriched diet might delay or prevent the neuronal loss in people with PINK1 associated Parkinson’s disease. They present data suggesting that beginning an intake of Folinic acid in early to middle stages of adulthood prevents the degeneration of dopamine neurons in pink1 mutant flies.

Folinic acid (also known as leucovorin) is a medication used to decrease the toxic effects of chemotherapy drugs. The pharmacokinetics of leucovorin suggests that it readily crosses the blood-brain-barrier (Source), so it would be possible for a clinical trial to be set up in human. Before taking that path, however, more testing is required (ideally in a mammalian model of Parkinson’s disease).

Amazing that all these results are coming from silly old flies though, huh?


The banner for today’s post was sourced from Tox.mrc.ac.uk

PARIS is always a good idea

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Audrey Hepburn was taking about the city when she uttered the words that title this post, but today we will be talking about the protein that bears the same name: PARIS.

Last week new research was published which demonstrated that in the absence of Parkin and Pink1 protein, the protein PARIS builds up and becomes toxic for cells.

Today’s post will review that research and we’ll discuss what it all means for Parkinson’s disease.


paris

No label required. A magnificent city. Source: HathawaysofHaworth

Today’s post has nothing to do with the city of Paris, but it is always nice to have photos of this European capital gracing the page.

We have recently discussed the Parkinson’s associated proteins Pink1 and Parkin (click here for that post). Today we will be revisiting these proteins as we discuss another protein that they interact with: PARIS (specifically PARIS1).

What is PARIS?

PARIS (aka TBC1D2 or TBC1 Domain Family Member 2) is a GTPase-activating protein.

What does that mean?

Getting a signal from outside of a cell into the interior is a complicated affair. There are numerous ways to do it, but one of the most common involves ‘G-proteins‘. These are involved with transmitting a signal from the outside of a cell into the interior, and when inside the cell G-proteins act as molecular switches.

G-proteins are located inside the cell membrane and are activated by G-protein-coupled receptors. When a signaling molecule binds to the G-protein-coupled receptor on the outside of the cell membrane, the portion of the receptor inside the cell activates the G-protein which then starts of a chain of events resulting in the signal being passed on.

11_07bgprotcoupledrec-l

Source: Bio1151

The role of GTPase-Activating Proteins in this process is to turn the G protein’s activity off. In step 4 of the image above, a GTPase-Activating Protein (which is not shown) binds to the G-protein and terminate the activity of the signalling event – returning it to an inactive state.

Thus, GTPase-Activating Proteins – like PARIS – are important regulators of signalling inside the cell.

What do we know about PARIS1 in Parkinson’s disease?

So a few years ago, a group of researchers led by Prof Ted Dawson at John Hopkins School of Medicine published this study:

cell

Title: PARIS (ZNF746) repression of PGC-1α contributes to neurodegeneration in Parkinson’s disease.
Authors: Shin JH, Ko HS, Kang H, Lee Y, Lee YI, Pletinkova O, Troconso JC, Dawson VL, Dawson TM.
Journal: Cell. 2011 Mar 4;144(5):689-702.
PMID: 21376232        (This article is OPEN ACCESS if you would like to read it)

In this study, the researchers noticed that the protein PARIS was accumulating in cells that did not have the Parkinson’s associated protein, Parkin. In those cells, the Parkin gene was mutated so that the Parkin protein was not produced properly. The researchers discovered that Parkin was important for labelling old PARIS protein for disposal. Thus in the absence of Parkin, PARIS protein would not be disposed of and simply piled up.

This build up of PARIS resulted in the loss of dopamine neurons in mice that did not produce Parkin. When the researchers re-introduced normal Parkin protein, the researchers were able to rescue the cell loss. Interestingly, the researchers also found that over production of PARIS in normal mice resulted in cell loss which could be rescued by a similar over production of Parkin.

When they looked in postmortem human brains, the researchers found that levels of PARIS protein were more than two times higher in regions affected by Parkinson’s disease (the striatum and the substantia nigra) of people with sporadic Parkinson’s disease when compared to healthy controls. Interestingly, this increase was only seen with PARIS protein, and not PARIS RNA (where the scientists saw no different with control samples), suggesting a build up of PARIS protein in the Parkinsonian brain.

The investigators concluded that this meant PARIS was could be playing a role in the cell loss associated with Parkinson’s disease.

They followed up this research a few years later with this publication:

parkins

Title: Parkin loss leads to PARIS-dependent declines in mitochondrial mass and respiration.
Authors: Stevens DA, Lee Y, Kang HC, Lee BD, Lee YI, Bower A, Jiang H, Kang SU, Andrabi SA, Dawson VL, Shin JH, Dawson TM.
Journal: Proc Natl Acad Sci U S A. 2015 Sep 15;112(37):11696-701.
PMID: 26324925     (This article is OPEN ACCESS if you would like to read it)

In this study, the same researchers found that when they remove the Parkin protein from the brains of adult mice there would be a decrease in the size and number of mitochondria. We have previous discussed mitochondria – the power stations of the cell – and their loss is bad news for a cell (click here to read more on mitochondria).

The researchers next demonstrated that this loss of mitochondria could reversed by removing PARIS protein from the Parkin mutant mice, and this prevented the loss of dopamine neurons. They also showed that the loss of mitochondria (and loss of dopamine neurons) could be caused by over production of PARIS in normal mice.

These results pointed towards an important role for both Parkin and PARIS in the maintenance of healthy mitochondria.

So what new research has been published about PARIS1?

This study was published last week:

dawson

Title: PINK1 Primes Parkin-Mediated Ubiquitination of PARIS in Dopaminergic Neuronal Survival.
Authors: Lee Y, Stevens DA, Kang SU, Jiang H, Lee YI, Ko HS, Scarffe LA, Umanah GE, Kang H, Ham S, Kam TI, Allen K, Brahmachari S, Kim JW, Neifert S, Yun SP, Fiesel FC, Springer W, Dawson VL, Shin JH, Dawson TM.
Journal: Cell Rep. 2017 Jan 24;18(4):918-932.
PMID: 28122242       (This article is OPEN ACCESS if you would like to read it)

In their study the researchers found that Parkin is not the only Parkinson’s associated protein in the PARIS story.

We have previously talked about the protein Pink1 (click here to read more on) – and yes, you would be forgiven if you start to think that all Parkinson’s related proteins start with the latter ‘P’. Pink1 grabs Parkin and causes it to bind to dysfunctional mitochondria. Parkin then signals to the rest of the cell for that particular mitochondria to be disposed of. In this study, the researchers found that Pink1 also grabs PARIS and signals for Parkin to dispose of it. In the absence of Pink1, normal Parkin protein does not label old PARIS protein for disposal and PARIS starts to pile up.

The researchers then began manipulating the levels of Pink in the brains of mice and they observed PARIS-dependent cell loss – that is to say, in the absence of Pink1, cells died only when PARIS was present.

These findings suggest that therapies targeting PARIS could be used in people with Parkinson’s disease who are carrying either a Parkin or a Pink1 mutation (both very common in early onset Parkinson’s disease).

What does it all mean?

People with early onset Parkinson’s disease quite often have a genetic mutation in one of a small number of genes – Pink1 and Parkin being prominent amongst these genes. The researchers who conducted the study that we have reviewed today have identified a common mechanism by which both of these proteins could be acting in their roles in Parkinson’s disease: a protein called PARIS.

Currently there is no treatment (that we are aware of) that targets the PARIS protein – nothing in the clinic nor being experimentally tested. Obviously, however, PARIS represents a VERY interesting protein for further investigations. The Dawson lab has several patents on PARIS (Click here and here for more on these), so evidently people will be working on drug candidates that inhibit PARIS.

There is a naturally occurring inhibitor, a micro RNA cluster miR-17-92 (also known as oncomir-1), which reduces the production of PARIS protein by blocking PARIS RNA (Click here for more on this). Using this micro RNA to target PARIS will be very difficult (both activating/delivering the micro RNA and unknown off target effects).

We are assuming that Prof Dawson and colleagues are rapidly screening compounds to determine which can block or inhibit PARIS activity and we will eagerly wait to see the results of that work.

Watch this space.


The banner for today’s post was sourced from Wallpapercave


EDITORIAL NOTE: Yay, 100 posts!

Niacin rich diets for Pink flies

pink_fly-1410843

Performer Miley Cyrus says that “Pink isn’t just a colour, it’s an attitude!”

Whether that is true or not is not for us to say.

What we can tell you is that ‘Pink’ is also a gene which is associated with Parkinson’s disease. And not just any form of Parkinson’s disease – people with early onset Parkinson’s (diagnosed before 40 years of age) often have specific mutations in this gene. And recently there has been new research published which may help these particular individuals.

Today’s post will review the new research and look at what it means for people with early onset Parkinson’s disease.


MJF-by-Seliger-May-2010-for-homepage-retouched_4

The actor Michael J Fox requires no introduction.

Especially in the Parkinson’s community where his Michael J Fox Foundation has revolutionised the funding and supporting of Parkinson’s disease research (INCREDIBLE FACT: Since 2000, The Michael J. Fox Foundation has funded more than US$450 MILLION of Parkinson’s disease research) and is leading the charge in the search for a cure for this condition.

Mr Fox has become one of the foremost figures in raising awareness about the disease that he himself was diagnosed with at just 29 years of age.

Wow, so young?

It is a common mistake to consider Parkinson’s disease a condition of the aged portion of society. While the average age of diagnosis floats around 65 years of age, it is only an average. The overall range of that extends a great distance in both directions.

Being diagnosed so young, Mr Fox would be considered to have early onset Parkinson’s disease.

What is early onset Parkinson’s disease?

Broadly speaking there are three basic divisions of Parkinson’s disease across different age ranges:

  • Juvenile-onset Parkinson disease – onset before age 20 years
  • Early-onset Parkinson disease – before age 50 years
  • Late-onset Parkinson disease – after age 50 years is considered

The bulk of people with Parkinson’s disease are considered ‘late-onset’. The Juvenile-onset version of the condition, on the other hand, is extremely rare but cases do pop up regularly in the media (For example, click here). We have previously written about Juvenile-onset Parkinson disease (Click here for that post).

Early-onset Parkinson disease is more common than the juvenile form, but still only makes up a fraction of the overall Parkinsonian population. Some of those affected call themselves 1 in 20 as this is considered by some the ratio of early-onset Parkinson’s compared to late-onset.

How prevalent is early onset Parkinson’s?

In 2009, Parkinson’s UK published a report on the prevalence of Parkinson’s disease in the UK.

Using the General Practice Research Database (GPRD), which houses information about 7.2% of the UK population (or 3.4 million people in 2009), Parkinson’s UK found that the frequency of Parkinson’s disease in the general public was 27 cases in every 10,000 people (or 1 person in every 370 of the general population). The prevalence is higher in men (31 in every 10,000 compared to 24 in every 10,000 among females)

Stats

Source: ParkinsonsUK

As you can see from the table above, the number of people affected by early onset Parkinson’s disease is small when compared to the late-onset population.

Officially, the prevalence of early onset Parkinson’s in Europe is estimated to be 1 in every 8,000 people in the general population (Source: Orphanet). This makes the population of affected individuals approximately 5-10 % of all people with Parkinson’s. Hence the 1 in 20 label mentioned above.

Like older onset Parkinson’s, males are more affected than females (1.7 males to every 1 female case). In addition, women generally develop the disease two years later than men.

So what does ‘Pink’ have to do with early onset Parkinson’s?

First, let’s have a look at ‘Pink’ the gene.

PTEN-induced putative kinase 1 (or PINK1; also known as PARK6) is a gene that is thought to protect cells. Specifically, Pink1 is believed to interact with another Parkinson’s disease-associated protein called Parkin (also known as PARK2). Pink1 grabs Parkin and causes it to bind to dysfunctional mitochondria. Parkin then signals to the rest of the cell for that particular mitochondria to be disposed of. This is an essential part of the cell’s garbage disposal system.

Hang on a second. Remind me again: what are mitochondria?

Mitochondria are the power house of each cell. They keep the lights on. Without them, the lights go out and the cell dies.

Mitochondria

Mitochondria and their location in the cell. Source: NCBI

You may remember from high school biology class that mitochondria are bean-shaped objects within the cell. They convert energy from food into Adenosine Triphosphate (or ATP). ATP is the fuel which cells run on. Given their critical role in energy supply, mitochondria are plentiful and highly organised within the cell, being moved around to wherever they are needed.

When a cell is stressed by a toxic chemical, the organisation of mitochondria breaks down (as is shown in the image below, where everything except mitochondria (in green) and the nucleus (blue) has been made invisible:

ampkmito-945x466

Mitochondria (green) in health cells (left) and in unhealthy cells (right).
The nucleus of the cell is in blue. Source: Salk Institute

In normal, healthy cells, PINK1 is absorbed by mitochondria and eventually degraded. In unhealthy cells, however, this process is inhibited and PINK1 starts to accumulate on the outer surface of the mitochondria. There, it starts grabbing the PARKIN protein. This pairing is a signal to the cell that this particular mitochondria is not healthy and needs to be removed.

601587-fig-003

Pink1 and Parkin in normal (right) and unhealthy (left) situations. Source: Hindawi

The process by which mitochondria are removed is called autophagy. Autophagy is an absolutely essential function in a cell. Without it, old proteins will pile up making the cell sick and eventually it dies. Through the process of autophagy, the cell can break down the old protein, clearing the way for fresh new proteins to do their job.

Think of autophagy as the waste disposal process of the cell.

So why is Pink1 important to Parkinson’s disease?

In 2004 this research article was published:

pink

Title: Hereditary early-onset Parkinson’s disease caused by mutations in PINK1
Authors: Valente EM, Abou-Sleiman PM, Caputo V, Muqit MM, Harvey K, Gispert S, Ali Z, Del Turco D, Bentivoglio AR, Healy DG, Albanese A, Nussbaum R, González-Maldonado R, Deller T, Salvi S, Cortelli P, Gilks WP, Latchman DS, Harvey RJ, Dallapiccola B, Auburger G, Wood NW.
Journal: Science. 2004 May 21;304(5674):1158-60.
PMID: 15087508

The researchers in this study were the first to report that mutations in the Pink1 gene were associated with increased risk of Parkinson’s disease. They found three families in Europe that exhibited a very similar kind of Parkinson’s disease and by analysing their DNA they determined that mutations in the Pink1 gene were directly linked to the condition.

They also looked at where in the cell Pink1 protein was located, noting the close contact with the mitochondria. In addition, they noted that the normal Pink1 protein provided the cell with protection against a toxic chemical, while the mutated version of Pink1 did not. These findings led the researchers to conclude that Pink1 and mitochondria may be involved in the underlying mechanisms of Parkinson’s disease.

And this initial study was quickly followed up 7 months later by this report:

dec-2004

Title: Analysis of the PINK1 gene in a large cohort of cases with Parkinson disease.
Authors: Rogaeva E, Johnson J, Lang AE, Gulick C, Gwinn-Hardy K, Kawarai T, Sato C, Morgan A, Werner J, Nussbaum R, Petit A, Okun MS, McInerney A, Mandel R, Groen JL, Fernandez HH, Postuma R, Foote KD, Salehi-Rad S, Liang Y, Reimsnider S, Tandon A, Hardy J, St George-Hyslop P, Singleton AB.
Journal: Arch Neurol. 2004 Dec;61(12):1898-904.
PMID: 15596610

In this study, the researchers analysed the Pink1 gene in 289 people with Parkinson’s disease and 80 neurologically normal control subjects. They identified 27 genetic variations, including a mutation in 2 unrelated early-onset Parkinson disease patients. They concluded that autosomal recessive mutations in PINK1 result in a rare form of early-onset Parkinson’s disease.

What does autosomal recessive mean?

Autosomal recessive means two copies of an abnormal gene must be present in order for the disease or trait to develop. That is to say, both parents will be carrying one copy of the mutation.

Mutations in the Pink1 gene have now been thoroughly analysed, with many mutations identified (the red and blue arrows in the image below). It is important, however, to understand that not all of those mutations are associated with Parkinson’s disease.

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Looks complicated. Genetic variations in the Pink1 gene. Source: APS

So how do mutations in the Pink1 gene cause Parkinson’s disease?

We believe that the mutations in the Pink1 DNA result in malformed Pink1 protein. This results in Pink1 not being able to do what it is supposed to do. You will remember what we wrote above: Pink1 grabs Parkin when mitochondria get sick and Parkin signals for that mitochondria is be disposed of. Well, in the absence a properly functioning Pink1, we believe that there is a build up of sick mitochondria and this is what kills off the cell. All Parkinson’s disease-associated mutations in the Pink1 gene inhibit the ability of Pink1 grab parkin (Click here for more on this).

And we see this in flies.

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Flies. Source: TheConservation

Flies (or drosophila) are a regular feature in biological research. Given their short life cycle, they can be used to quickly determine the necessity and function of particular genes. Yes, they are slightly different to us, but quite often the same biological principles apply.

Take Pink1 for example.

When scientists mutate the Pink1 gene in flies, it leads to the loss of flight muscles and male sterility. These effects both appear to be due to the kind of mitochondrial issues we were discussing above. One really amazing fact is that the human version of Pink1 can actually rescue the flies that have their Pink1 gene mutated. This is remarkable because across evolution genes begin to differ slightly resulting in some major differences by the time you get to humans. The fact that Pink1 is similar between both flies and humans shows that it has been relatively well conserved (functionally at least).

And given that we see similarities in the Pink1 gene and function between flies and humans, then perhaps we can apply what we see in flies to humans with regards to treatments.

Which brings us (finally!) to the research paper we wanted to look at today:

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Title: Enhancing NAD+ salvage metabolism is neuroprotective in a PINK1 model of Parkinson’s disease<
Authors: Lehmann S, Loh SH, Martins LM.
Journal: Biol Open. 2016 Dec 23. pii: bio.022186.
PMID: 28011627              (this article is OPEN ACCESS if you would like to read it)

In this study, the researchers analysed Pink1 flies and found alterations in the activity of an enzyme called nicotinamide adenine dinucleotide (or NAD+). NAD+ is one of the major targets for the anti-aging crowd and there is some very interesting research being done on it (Click here for a good review on this). NAD+ is a coenzyme found in all living cells. A coenzyme functions by carrying electrons from one molecule to another (Click here for a nice animation that will explain this better). The researchers found that Pink1 mutant flies have decreased levels of NAD+.

The researchers were curious if a diet supplemented with the NAD+ would rescue the mitochondrial defects seen in the Pink1 mutant fly. Specifically, they fed the flies a diet high in the NAD+ precursor nicotinamide (being a precursor means that nicotinamide can be made into NAD+ once inside a cell). They found that not only did nicotinamide rescue the mitochondrial problems in the flies, but it also protected neurons from degeneration.

So why is the title of this post talking about Niacin and not nicotinamide?

Niacin (also known as vitamin B3 or nicotinic acid) – like nicotinamide – is also a precursor of NAD+. And in their discussion of the study, the researchers noted that a high level of dietary niacin has been associated with a reduced risk of developing Parkinson’s disease (Click here and here for more on this).

The researchers were quick to point out that while a high Niacin diet may be beneficial, it could not be considered a cure in anyway for people with Parkinson’s disease because although it may be able to slow the cell death it would not be able to replace the cells that have already been lost.

So what does it all mean?

Hang on a second. We’re not finished yet.

Numerous media outlets have made a big fuss about the Niacin diet angle to this research, and they have ignored another really interesting finding:

In their study the researchers mutated another gene in the Pink1 flies which also resulted in improved mitochondrial function and neuroprotection. That gene was Poly (ADP-ribose) polymerase (or PARP). Parp is an enzyme involved in DNA repair and cell division. It is produced in very high levels in many types of cancer and medication that inhibit or block Parp are being tested in the clinic as therapies in those cancers.

Interestingly, blocking Parp has been previously shown to be beneficial for cell survival in models of Parkinson’s disease (Click here and here for more information on this). So in addition to changing to a high niacin diet, it would be interesting to follow up this results as well.

Particularly for people with the Pink1 mutation.

And this is where the results of this study are particularly interesting: they may relate specifically to a small population within the Parkinson’s community – those with Pink1 mutations. It would be interesting to begin discussing and designing clinical studies that focus particularly on people in this population (similar to the Ambroxol study – click here for our post on this).

So what does it all mean? (again)

The results of the present study demonstrate two means by which people with a particular genetic mutation could be treated for Parkinson’s disease. Obviously further research is required, but the idea that we are approaching an age in Parkinson’s disease research where treatments could be personalised is very appealing. It will be interesting to see where all of this goes.


EDITOR’S NOTE:  If nothing we have written here makes any sense, then maybe this video will help:


The banner for today’s post was sourced from Wallpapersinhq