Amyloid β-protein and Synaptophysin

Amyloid β-peptide is normally produced in the brain from the amyloid precursor protein (APP). The amyloid cascade hypothesis of Alzheimer disease says that abnormal accumulation in the brain of amyloid β-peptide () causes disruption of synaptic neurotransmission and, eventually, the death of neurons and Alzheimer disease (see the image below).

Amyloid Cascade Hypothesis

During the past 20 years there has been a large amount of research into the normal physiological role of APP and the idea that  can disrupt synaptic neurotransmission.

In a previous blog post I mentioned that the WNT signaling pathway has been implicated in memory storage. There is evidence that the enzyme glycogen synthase kinase 3β (GSK-3β) is involved in memory deficits seen in Alzheimer disease.

A recently published article provides evidence that 42 binds to the synaptic vesicle protein synaptophysin42 disrupts the complex that is normally formed between synaptophysin and VAMP2 altering the way that neurons handle their synaptic vesicles.

If Aβ42 is involved in synaptic transmission by modulating several pre- and postsynaptic mechanisms then such research can identify potential targets for pharmacological intervention against age-associated memory loss.

In a previous blog post I mentioned the synaptic vesicle protein synaptogyrin-3. Synaptophysins and synaptogyrins are members of the tetraspan
vesicle membrane protein family and constitute major secretory vessicle proteins that bind to many other vessicle-associated proteins.

Related reading: The Alzheimer’s amyloid-degrading peptidase, neprilysin: can we control it?

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Regulation of Monoamine Oxidase in Parkinson Disease

Parkin regulated protein turnover.

In an earlier blog post I linked to an article about the potential role of dopamine metabolism and oxidative stress in Parkinson disease. Now the research group of Jian Feng reports that the protein Parkin regulates the expression of monoamine oxidase in human dopaminergic neurons (Parkin controls dopamine utilization in human midbrain dopaminergic neurons derived from induced pluripotent stem cells).

As early as 2003, experiments in mice linked low levels of Parkin to increased metabolism of dopamine by monoamine oxidase (1). One of the existing treatments for Parkinson Disease is inhibition of monoamine oxidase (see: “The role of rasagiline in the treatment of Parkinson’s disease“).

Feng’s group started with skin cells from human patients with mutated Parkin genes. They made pluripotent stem cells from the skin cells and then induced the stem cells to differentiate into dopaminergic neurons for use in their studies of the role of Parkin in human neurons.

Parkinson Disease patients with defective Parkin genes might particularly benefit from treatment with monoamine oxidase inhibitors.

Image source: European Iron Club.

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I finally used ProfCast software to add audio tracks to PowerPoint presentations.

screenshot of ProfCast interface
ProfCast recording interface

This image (to the right) shows the ProfCast interface after drag/drop of the “Diffusion and Osmosis problem 1” PowerPoint presentation into the ProfCast window. Here is a link to the PowerPoint pptx file:

Diffusion and Osmosis problem 1

While you use ProfCast to record audio for the presentation, it creates PNG image files for each slide in the PowerPoint presentation.

Slide count and status

Slide count and status

ProfCast will also save an audio file. The audio format is ADTS. You can save your combined images and audio as an m4a format podcast or as a QuickTime movie (.mov) file.

Audio input for HP 6450b

Default audio input for HP 6450b

I started recording audio for the Diffusion & Osmosis problem set with the default settings and internal microphone on an HP 6450b.

For an alternative way to record audio, I used the Macintosh GarageBand application and the built-in microphone on a Apple iMac. Here is a screenshot of the podcasting interface for GarageBand:


GarageBand podcasting interface









In the image above, you can see how GarageBand lets you work with multiple image and audio tracks. The image track for the podcast is at the top (Podcast Track). I used the “Male Voice” track to record my narration for the PowerPoint slides. I also used a music track (Jingles) to add in a musical transition between each image.

My goal was to make movie files for upload to YouTube, so I exported my audio from GarageBand and made QuickTime movies using Apple’s iMovie application. Here (below) is the first two movie (YouTube playlist). The movie has audio that was recorded  by an iMac.

I’ll probably be satisfied to just use GarageBand and the built-in iMac microphone for recording audio, but I wonder if I could get significantly better quality voice recordings by using a headset.

I have some background noise (hiss) when recording my voice audio if both the iMac and the HP laptop are running. I used the GarageBand noise filter to remove some of the background noise:

Noise reduction in GarageBand

Noise reduction in GarageBand

Related blog post: using animated pointers in a narrated PowerPoint presentation.

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Prezi presentation software

Is Prezi more useful than PowerPoint?

Testing Prezi on Prezi

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Medical Student Bridge Program

I had a chance to observe the University of Arizona Medical Student Bridge Program. We would like to start a similar program at SCNM in order to help “nontraditional” medical students get ready for their first quarter of medical school.

Since I never went to medical school, I am not very good at providing medical students with advice for how to survive in medical school. I’ve long been amazed by the vast amount of information that medical students are able to learn and apply. I benefitted from seeing how the U of A Bridge program advises its new students about how to remember, integrate and use information from their basic science classes.

One of the U of A students that I spoke to said that he was a mathematics major as an undergraduate and that he had never really needed to study previously since mathematics came naturally to him. I had a similar experience in my schooling, being able to select and attend only the classes that I was interested in and not being subjected to a flood of information.

I’ve long had an interest in learning and memory, so I’m familiar with the importance of repetition and the idea that we can all benefit from thinking about information while using multiple sensory modalities. When I was in school I never found it useful to study with someone else. There always seemed to be a temptation to goof off and not study or one person would understand the material and be bored while the other might just be bored with the topic and not understand it.

In the U of A Bridge Program there is an emphasis on the students working together with a partner to either preview material before a lecture or review the information from a lecture that has already been attended. I can see that if medical students follow this approach then they will experience useful repetition while they read, listen to, write and talk about the subject matter. Yet another learning option provided in the U of A medical school is practice exams. Rather than being provided with prectice questions in the form of question sets at the end of textbook chapters or in a board review book, all of the U of A exams and practice questions are online as part of their U of A medical school learning resources.

I’d be interested to hear from SCNM students who can answer this question: What do you now know about how to survive in medical school that you wish you had been told before day 1 of the first quarter?

Related reading

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Functions of dopamine in the basal ganglia

Direct and indirect motor pathways

Direct and indirect motor pathways in the basal ganglia

Parkinson disease can be caused by loss of dapaminergic neurons in the substantia nigra. There are two major populations of neurons in the striatum that respond to dopamine. Their roles in movement disorders are the subjuct of ongoing research.

I previously mentioned the article “Distinct subclasses of medium spiny neurons differentially regulate striatal motor behaviors” which describes experiments in mice that test the current model of how the basal ganglia control movement.

In current models of motor control by the basal ganglia, a distinction is made between a population of type 2 dopamine receptor (D2R) expressing neurons and a population of D1R expressing neurons (see the figure, above right).

By using the gene expression control regions of the D2 and D1 receptors, Bateup et al. were able to selectively disrupt expression of DARPP-32 in either the D2R- or D1R-expressing striatal neurons of mice. DARPP-32 is an important protein for many of the normal actions of dopamine in the brain, including those in the striatum. When DARPP-32 levels were reduced selectively in the D2R-expressing striatal neurons, the mice showed increased locomotor activity. Reduced DARPP-32 in D1R-expressing striatal neurons resulted in reduced basal locomotor activity, consistent with the standard model in which  the direct pathway normally exerts a stimulatory effect on locomotion.

Such “proof of concept” experiments in mice raise hope for future interventions that might allow selective modulation of the direct and indirect pathways in humans. This might help solve problems such as development of dyskinesias following long-term use of L-DOPA or cell transplant therapy in Parkinson disease patients.

Posted in dyskinesia, Huntington disease, L-DOPA, Parkinson disease | Tagged , , , | 1 Comment

Journal Club

Dopamine transport

Dopamine transport proteins VMAT2 and DAT. (public domain illustration by John Schmidt)

I’m trying to establish a more formal system for a “journal club”, but for now we can use this blog. [Update, Spring 2012, see this journal club page.]

This blog post starts the “journal club”. “Journal club” means that participants will each pick a topic and find a related journal article.

Here I introduce the article called, “Physical and Functional Interaction between the Dopamine Transporter and the Synaptic Vesicle protein Synaptogyrin-3“.

This journal article is medically important because many pharmacological agents alter dopamine (DA) transport and brain function. Methamphetamine is a major drug of abuse and it disrupts normal dopamine transport, but the exact mechanism is still mysterious. As shown in the diagram, two major dopamine transport proteins are DAT and VMAT2. DAT normally allows for re-uptake of dopamine from the synaptic cleft. VMAT2 is important for transport of dopamine from the cytoplasm into synaptic vesicles.

Egaña et al. report some experiments suggesting that there might be a complex of physically interacting proteins including DAT, synaptogyrin-3, and VMAT2. Synaptogyrin-3 is a synaptic vesicle protein. It was also recently suggested that VMAT2 forms a protein complex with tyrosine hydroxylase (TH) and aromatic amino acid decarboxylase (AADC, also called DOPA-decarboxylase).

Why is this medically important? Amphetamines cause depletion of dopamine from synaptic vesicles. If DAT and VMAT2 are physically linked then it might be that amphetamine binding to cell surface transporters like DAT can alter the function of VMAT2. VMAT2 seems to be the binding site for chemicals such as lobelane that can inhibit methamphetamine-evoked DA release from neurons. There might be a previously unrecognized macromolecular complex of proteins linking cell surface transport proteins such as DAT to VMAT2. If such a complex of linked dopamine transport proteins does exist, study of how DAT and VMAT2 interact might help us better understand medical conditions such as Parkinson disease, dystonia, depression, schizophrenia, attention-deficit hyperactivity disorder (ADHD), Tourette syndrome, and drug addiction.

Note: The current conventional thinking about how methamphetamine alters dopamine storage and transport does not involve any physical link between the cell surface DAT and synaptic vesicles.

Related reading.  A Receptor Mechanism for Methamphetamine Action in Dopamine Transporter Regulation in Brain

Is Parkinson’s disease a vesicular dopamine storage disorder? J. Neurosci. 2014 June

Comments are welcome here about the article “Physical and Functional Interaction between the Dopamine Transporter and the Synaptic Vesicle protein Synaptogyrin-3” and dopamine transport in the brain.

If you want to participate in the “journal club”,  find a recently published journal article and prepare a brief written account of why the article is of interest to you. Contact me and I can make it possible for you to post and share your contribution to the “journal club” here in blog format.

Posted in L-DOPA, membrane transport | Tagged , , | 5 Comments