Tag: ubiquitin

The age-associated changes of PARKIN

~ Simon ~ 4 Comments

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Tiny variations in a region of DNA referred to as “Parkin” are associated with an increased risk of developing Parkinson’s (particularly young onset forms of the conditions). The Parkin DNA provide the instructions for making a protein that is involved with many functions inside cells.

New research indicates that as we age, Parkin protein becomes less available. In fact, by the time we turn 50 years of age, “Parkin is largely insoluble”, meaning that the majority of the protein is no longer able to do its job.

This shift appears to involve oxidation changes.

In today’s post, we will discuss what Parkin and oxidation are, how Parkin might be affected by oxidation, and how this information might be useful to treating Parkin-associated Parkinson’s.

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Me (I wish) before 27. Source: Pinterest

I don’t know about you, but 27 was my peak.

Before my 27th birthday, I could run around all over the place – acting like an idiot, with all the energy in the world. I was invincible and having lots of fun. And yes, some vices might have been involved – I would drink myself blind on a Friday night, wake up fresh the next day and do it all merrily again.

Me before 27. Source: Thefix

But then, my 27th birthday came along and I woke up the next day tired and feeling… fatigued. Weary even. And definitely with less enthusiasm than I had before I passed out the night before. My father called it a “hang-over” (which up until that time I had naively/idiotically thought I was immune to).

Me, before (left) and after 27 (right). Source: Wanna-joke

But I gradually developed this sinking feeling that it was something else.

Something more sinister.

It was as though something had changed. Something inside of me.

And I distinctly remember a moment of realisation, when I asked “Am I getting old???”

My father saw my concern and gave me sage advice (“It’s like I always say, aging ain’t for sissies“), and with that I changed my ways.

Source: DS

Since that moment, I have been fascinated by the biology of aging, particularly in the context of Parkinson’s (age is the main correlate with neurodegenerative conditions like Parkinson’s and Alzheimer’s). So it was with great interest that I read a manuscript in November last year that had been posted on the openly-available preprint database bioRxiv.

What did the manuscript say?

Continue reading “The age-associated changes of PARKIN” →

Putting the PARKIN back into Parkinson’s

~ Simon ~ 3 Comments

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Genetic variations in a region of our DNA called PARKIN is associated with an increased risk of developing Parkinson’s – particularly young-onset PD (diagnosed before the age of 40yrs).

This area of DNA provides the instructions for making a protein (also referred to as PARKIN), which plays a number of important roles inside of cells.

Recently, a South Korean biotech company called Cellivery has published research on an experimental therapeutic agent that easily penetrates both the brain and cells within, delivering PARKIN protein to the cells that need it.

In today’s post, we will discuss what PARKIN does, review the new research report, and explore what could happen next.

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Source: Quanta

Here on the SoPD we often talk about research regarding the prominent Parkinson’s associated proteins, think of alpha synuclein, LRRK2 and GBA. And they are of interest as there is a great deal of activity now at the clinical level exploring agents targetting these proteins.

But there are a number of interesting therapeutics being developed that are exploring some of the other Parkinson’s-associated proteins.

A good example was published this week:

Title: Intracellular delivery of Parkin rescues neurons from accumulation of damaged mitochondria and pathological α-synuclein
Authors: Chung E, Choi Y, Park J, Nah W, Park J, Jung Y, Lee J, Lee H, Park S, Hwang S, Kim S, Lee J, Min D, Jo J, Kang S, Jung M, Lee PH, Ruley HE & Jo D
Journal: Science Advances, 29 Apr 2020:6, 18, eaba1193
PMID: N/A

In this study, South Korean researchers demonstrated that a brain penetrating compound (including the PARKIN protein) can rescue numerous models of Parkinson’s.

Hang on a second: What is PARKIN?

Continue reading “Putting the PARKIN back into Parkinson’s” →

DUBstop: Oxford-style

~ Simon ~ 5 Comments

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This week multiple research groups at the University of Oxford and Boston-based FORMA Therapeutics announced a collaboration to identify, validate and develop deubiquitinating enzyme (DUB) inhibitors for the treatment of neurodegenerative conditions, like Parkinson’s.

But what exactly are DUB inhibitors? And how do they work?

In today’s post, we will answer these questions, look at what the new collaboration involves, and look at what else is happening with DUB inhibitors for Parkinson’s.

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Source: Blog4dubstep

Dubstep is a genre of electronic dance music that originated in South London in the late 1990s. Only recently -in the 2010s – has the culture really become more mainstream. And while I have a hard time appreciating the heavy bass music (man, I am becoming a grumpy old man before my time), it is amazing to watch some of the dancers who robotically embody this form of music:

The guy on the right is named Marquese Scott. Sometimes he simply defies the laws of physics.

The title of today’s post is a play on words, because rather than doing ‘Dubstep’ we are going to be discussing how to ‘DUB-stop’.

Researchers in Oxford have recently signed an agreement with a US company to focus resources and attention on a new approach for tackling neurodegenerative conditions, including Parkinson’s.

What they are proposing is a complicated biological dance.

Their idea: to stop deubiquitinating (DUB) enzymes.

What are deubiquitinating enzymes?

Continue reading “DUBstop: Oxford-style” →

Novartis focuses on improving PARKIN control

~ Simon ~ 8 Comments

Last week, as everyone was preparing for Christmas celebrations, researchers at the pharmaceutic company Novartis published new research on a gene that is involved with Parkinson’s, called PARKIN (or PARK2).

They used a new gene editing technology – called CRISPR – to conduct a large screening study to identify proteins that are involved with the activation of PARKIN.

In today’s post we will look at what PARKIN does, review the research report, and discuss how these results could be very beneficial for the Parkinson’s community.

Source: Novartis

As many people within the Parkinson’s community will be aware, 2017 represented the 200th anniversary of the first report of Parkinson’s disease by James Parkinson.

It also the 20th anniversary of the discovery of first genetic mutation (or variant) that increases the risk of developing Parkinson’s. That genetic variation occurs in a region of DNA (a gene) called ‘alpha synuclein’. Yes, that same alpha synuclein that seems to play such a critical role in Parkinson’s (Click here to read more about the 20th anniversary).

In 2018, we will be observing the 20th anniversary of the second genetic variation associated with Parkinson.

That gene is called PARKIN:

Title: Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism.
Authors: Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S, Yokochi M, Mizuno Y, Shimizu N
Journal: Nature. 1998 Apr 9; 392(6676):605-8
PMID: 9560156

In 1998, Japanese researchers published this report based on 5 individuals from 4 Japanese families who were affected by juvenile-onset Parkinson’s. In family 1, the affected individual was a female, 43 years old, born of first-cousin parents, and her two younger brothers are healthy. Her condition was diagnosed in her teens and it had then progressed very slowly afterwards. Her response to L-dopa was very positive, but L-dopa-induced dyskinesia were frequent. In family 2-4, affected individuals (born to unrelated parents) exhibited very similar clinical features to the subject in family 1. The age of onset was between 18 to 27 years of age.

Using previous research and various techniques the investigators were able to isolate genetic variations that were shared between the 5 affected individuals. They ultimately narrowed down their search to a section of DNA containing 2,960 base pairs, which encoded a protein of 465 amino acids.

They decided to call that protein PARKIN.

PARKIN Protein. Source: Wikipedia

How much of Parkinson’s is genetic?

Continue reading “Novartis focuses on improving PARKIN control” →

Are Lewy bodies fake news?

~ Simon ~ 21 Comments

One of the cardinal features of the Parkinsonian brain are dense, circular clusters of protein that we call ‘Lewy bodies’. 

But what exactly are these Lewy bodies?

How do they form?

And what function do they serve?

More importantly: Are they part of the problem – helping to cause of Parkinson’s? Or are they a desperate attempt by a sick cell to save itself?

In today’s post, we will have a look at new research that makes a very close inspection of Lewy bodies and finds some interesting new details that might tell us something about Parkinson’s.

Neuropathologists conducting a gross examination of a brain. Source: NBC

A definitive diagnosis of Parkinson’s disease can only be made at the postmortem stage with an examination of the brain. Until that moment, all cases of Parkinson’s disease are ‘suspected’.

When a neuropathologist makes an examination of the brain of a person who passed away with the clinical features of Parkinson’s, there are two characteristic hallmarks that they will be looking for in order to provide a final diagnosis of the condition:

1.  The loss of specific populations of cells in the brain, such as the dopamine producing neurons in a region called the substantia nigra, which lies in an area called the midbrain (at the base of the brain/top of the brain stem).

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The dark pigmented dopamine neurons in the substantia nigra are reduced in the Parkinson’s disease brain (right). Source:Memorangapp

2.  Dense, circular clusters (or aggregates) of protein within cells, which are called Lewy bodies.

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A cartoon of a neuron, with the Lewy body indicated within the cell body. Source: Alzheimer’s news

What is a Lewy body?

A Lewy body is referred to as a cellular inclusion (that is, ‘a thing that is included within a whole’), as they are almost always found inside the cell body. They generally measure between 5–25 microns in diameter (5 microns is 0.005 mm) thus they are tiny, but when compared to the neuron within which they reside they are rather large (neurons usually measures 40-100 microns in diameter).

A photo of a Lewy body inside of a neuron. Source: Neuropathology-web

How do Lewy bodies form? And what is their function?

The short answer to these questions is:

Source: Wellbeing365

The longer answer is: Our understanding of how Lewy bodies are formed – and their actual role in neurodegenerative conditions like Parkinson’s – is extremely limited. No one has ever observed one forming. Lewy bodies are very difficult to generate in the lab under experimental conditions. And as for their function, this is the source of much guess work and serious debate (we’ll come back to this topic later in this post).

Ok, but what are Lewy bodies actually made of?

Continue reading “Are Lewy bodies fake news?” →