in which more evidence accumulates for utility of calcium channel blockers in treating Parkinson's disease

Neurodegeneration in Parkinson's disease is known to be specific to a group of dopamine neurons originating in the substantia nigra pars compacta (SNpc).  In  nearby region, the ventral tegmental area (VTA), dopamine neurons are all but unaffected by disease progression.  This selectivity has generated great interest from the PD research community.  In  a study out of Dr. D. James Surmeier's lab at Northwestern University, this selectivity was suggested to be related to calcium channel activity.

 Neural pacemaking, or the rhythmic signalling common to neurons in the motor circuit, involves the influx of calcium into the cell.  Pacemaking in juvenile SNpc dopamine neurons is similar to neurons in the VTA.  However, in mature SNpc neurons pacemaker firing opens many more L-type calcium channels than in VTA neurons.  This allows for greater influx of calcium to the cell, and puts a greater burden on the mitochondrial system in order to pump it out, fostering oxidative stress.  Therefore, basal oxidative stress is thought to be significantly higher in SNpc compared to VTA dopamine neurons.

The Surmeier team wanted to confirm the importance of the L-type calcium channel in producing the differences in oxidative stress levels between SNpc and VTA neurons.  In order to do this, they used a genetic knockout model of DJ-1 (or Park7), the popular gene linked to occurance of familiar Parkinson's disease.

In a beautiful study, they recorded intracellular calcium oscillations and oxidation of mitochondrial matrix proteins from SNpc dopamine neurons in mice with or without the DJ-1 gene, and found that oxidative stress was greater in SNpc neurons in DJ-1 knockouts compared to wild type.  They also showed that pretreatment with isradipine, an L-type calcium channel agonist, kept DJ-1 knockout oxidative stress levels near wild type levels.

The study also suggests that mitochondrial uncoupling protein (UCP) expression is greater in SNpc dopamine neurons compared to VTA, resulting in more frequent mitochondrial 'flickering', or transient depolarization.  In DJ-1 knockout mice, UCP expression was lower, suggesting that UCP expression in SNpc dopamine neurons contributes to oxidative stress.

Collectively, the restuls of the study indicate that high calcium entry to SNpc dopamine neurons through L-type channels during pacemaking activity leads to selectively elevated oxidative stress.  In turn, these SNpc dopamine neurons are made more susceptible to toxins, aging and the degenerative effects of DJ-1 mutations.  Several calcium blockers are currently used to treat conditions like cardiomyopathy and kidney disease, btu the current study suggests their use in Parkinson's disease in order to protect against oxidative stress to which these mature neurons are so vulnerable.


Guzman JN, Sanchez-Padilla J, Wokosin D, Kondapalli J, Ilijic E, Schumacker PT, & Surmeier DJ (2010). Oxidant stress evoked by pacemaking in dopaminergic neurons is attenuated by DJ-1. Nature, 468 (7324), 696-700 PMID: 21068725

an instance of misconstrued media reporting: placebos

A most recent example of the media mis-representing scientific findings is the recent NPR report on placebos being equally effective in IBS patients as "the strongest prescription drugs", even when the patients knew that they were being given the placebo.  This coverage was a translation of a study out of Harvard Medical, and published in PLoS ONE.


The study, termed "honest placebo", didn't actually eliminate the deception for which placebo studies are renowned.  In the methodology, the researchers report telling the patients who received placebo treatment that “placebo pills, something like sugar pills, have been shown in rigorous clinical testing to produce significant mind-body self-healing processes.”  By this design, the patients may have received a similar benefit to what they would have experienced if they had expected that they were being given a strong prescription drug.  The patients were given the impression that the placebo would help them.  What would have contributed even greater meaning to this study is an additional group who were told that they were receiving a placebo drug, but not told that it was expected to help them.


As many of the comments on the NPR report echo, a strong component in placebo studies is the idea of holism and self-healing.  Dr. Ted Kaptchuk, a co-investigator in the Harvard study, states in his interview that the healing factor was assumed to be the "self-healing ritual" of dosing oneself twice daily, even with a placebo.  This scientist would suggest that self-healing is as likely to take place due to the belief that a placebo had been reported helpful as it is to be due to the ritual of pill-taking.


The great value of this study's conclusions is lost in the media translation: there is healing potential in having the expectation that your therapy will work. 
 NPR does the courtesy of acknowledging that "placebos don't shrink tumors or stop multiple sclerosis in its tracks".  However, particularly for conditions such as IBS, which have consistently shown to be negatively effected by stress and proactive treatment, this study's findings are important to treatment development.


Ted J. Kaptchuk, Elizabeth Friedlander, John M. Kelley, M. Norma Sanchez, Efi Kokkotou, Joyce P. Singer, Magda Kowalczykowski, Franklin G. Miller, Irving Kirsch, Anthony J. Lembo (2010). Placebos without Deception: A Randomized Controlled Trial in Irritable Bowel Syndrome PLoS

VEGF-B as a therapeutic intervention for Parkinson's disease

Since it was discovered that the brain had tremendous neuroregenerative potential, growth factors have been highly speculated as therapeutic tools.  The vascular endothilial growth factor (VEGF) family, and particularly VEGF-B, has recently been distinguished as having a neuroprotective role in the Parkinsonian brain.

Carolina Hagberg et al. published the findings in Nature Letters earlier this year that VEGF-B was tightly co-expressed with several mitochondrial genes, suggesting a role for this growth factor in metabolism.  VEGF-B was specifically found to regulate endothilial fatty acid transport (uptake) proteins, and thus, the uptake of fatty acids into peripheral and heart muscle, and brown adipose tissue.  The co-expression of VEGF-B and mitochondrial proteins suggests a coordination of endothilial lipid uptake and mitochondrial lipid use, which is why it is an attractive intervention for PD, wherein it is thought that dopaminergic neurons die by dysfunction of mitochondrial metabolism.

This mechanistic information provides support for work lead by Torsten Falk at the University of Arizona suggesting a role for VEGF-B in the Parkinsonian brain.  In a 2009 study, a midbrain cell culture showed upregulation of the VEGF-B gene following treatment with rotenone (a pesticide specifically toxic to dopaminergic neurons, and commonly used in non-primate animal models of PD).  Additionally, application of exogenous VEGF-B to cell cultures resulted in neuroprotection from rotenone toxicity.

More recently, Falk et al. have shown exogenous VEGF-B to be neuroprotective in vivo.  From a 2006 study by Sun et al., intraventricularly administered VEGF-B restored neurogenesis to wild-type levels in VEGF-B knockout mice.

In corroboration with the Hagberg study, there is a strong suggestion that VEGF-B may be neuroregenerative via direct effect on mitochondrial function.  Correlative studies associating VEGF-B expression with midbrain mitochondrial un-coupling proteins, Complex I, or apoptotic cascades remain to be seen.  Additionally, there are no reports of VEGF-B's capacity to be neurorestorative, or slow dopaminergic neurodegeneration in a progressive PD model.


Hagberg, C., Falkevall, A., Wang, X., Larsson, E., Huusko, J., Nilsson, I., van Meeteren, L., Samen, E., Lu, L., Vanwildemeersch, M., Klar, J., Genove, G., Pietras, K., Stone-Elander, S., Claesson-Welsh, L., Ylä-Herttuala, S., Lindahl, P., & Eriksson, U. (2010). Vascular endothelial growth factor B controls endothelial fatty acid uptake Nature, 464 (7290), 917-921 DOI: 10.1038/nature08945

T. A. FALK, X. YUE, S. ZHANG, S. J. SHERMAN (2010). Evidence for neuroprotection after treatment with Vascular Endothelial Growth Factor-B in vivo in the 6-hydroxydopamine rat model of Parkinson’s disease Society for Neuroscience 2010 Abst.

Sun, Y., Jin, K., Childs, J., Xie, L., Mao, X., & Greenberg, D. (2006). Vascular endothelial growth factor-B (VEGFB) stimulates neurogenesis: Evidence from knockout mice and growth factor administration Developmental Biology, 289 (2), 329-335 DOI: 10.1016/j.ydbio.2005.10.016

SfN 2010 Take-aways

Things that I learned from posters, presentations and lectures at SfN this year will play themselves out in my research and career direction, but there were other notables which were not so directly translatable.  Here are my not-necessarily-scientific take-aways from SfN 2010:

1.  Had anyone told me growing up that learning multiple languages with any degree of volubility would be very important in my communication with other scientists, I would have put more effort into Spanish, German and French.  Four years of Latin does me worlds of good in reading, but in deciphering various accents and breaking language barriers... repetition and speaking loudly were my only saving tools last week.  It is very humbling that all of these wonderful minds, to whom English is a second language, have learned it so fluently.

2.  Although it was immense fun to spend a week on a yacht in a nearby harbor, I think that I would have gotten more out of staying closer to the convention center.  By the time 7pm approached and I had mosied back to my boat, had a bite to eat (on those nights when we did not go out to eat) and relaxed, another twenty minute drive back to the convention center area for any of the satellite events was less appealing.  ... and I do regret missing out on some of those -- thank goodness for Neuroblogger reports!

3.  Limiting my content was certainly helpful, and the best approach for me.  What happened was that I made sure that I got to everything on my list, and then ventured out into other subfields (olfaction, methodologies, learning and memory).  Next year, I think I will venture even further, as I still limited this extended content to its relation to my methodologies, or my circuits, or my disease.

4.  Taking two afternoons to explore the city was essential.

SfN 2010: Tuesday

Tuesday was the biggest day of the conference, for me.  While I maintained my initial pace during poster sessions, I soon discovered that on days when those posters were scattered throughout the convention hall, my body was substantially more taxed by the end of the day.  Tuesday was no exception, as the morning encompassed introducing myself via poster speculation to three potential mentors, each in a different subtopic of the session.

I succeeded in making a fool of myself in introduction to one such PI, by attempting to hide behind other poster surveyors until I was equipped with intelligent questions about his research.  My scheme unraveled when he recognized the name on my badge and made the introduction himself.  I spun a subterfuge of embarrassed chatter until recovering my intellect.  Fortunately, he stopped by my poster in the afternoon and was enthusiastic and impressed.  Score.

A dear late post doc of our neighboring lab, now working in industry as a medical liaison, imparted some wisdom regarding the giant that is SfN.  "What is unique about this conference," she said, "is that what your experience here changes each year as your career changes."  When you are a graduate student, your mission is to soak up any and all information about other research that may help design your own.  When you are a post doc, you are sponging in addition to networking.  When you are a PI, you are peppering your collaborative learning with reunions and lunch dates.  In industry, she says, you are honing in on studies where drug intervention studies may be beneficial for your company, as well as attending committee meetings.  SfN is consistently a whole 'nother world  defined by where you are outside of it.

And, I suppose, as a pre-pre-doc, my mission this year was to get my feet wet, to network, to get some face time with potential mentors and, of course, benefit from poster feedback on my own research.  In all of these regards, I believe I was successful.

Tuesday afternoon was my poster session, and though I initially planned on holding the fort for two of the four hours, both my boss and myself were present for almost the entire session breaking away for no more than half an hour each to visit other posters.  Thank goodness for my wonderful colleague who fielded questions in our brief absences even though she works with a different model!  By half an hour into the session, the traffic in front of our poster was boggling.  My boss and I ended up tag-teaming presentation/question rounds for different handfuls of people. The feedback was spectacular, with several unique directions offered, several potential collaborations resulting and a few friends made.

What's more, I was totally starstruck by the flow of big names in front of our poster whose badges I recognized from manuscripts that had jump-started my career or helped to define my work, but whose faces were met for the first time.  At one point I remember surreptitiously asking my boss, "is that the Mike Salvatore?"  What a rush to present and discuss your work with minds whose contributions to neuroscience have shaped your own, and what an even greater honor to be commended by them for your ideas.  These folks are all friends of my boss -- you come to know or at least meet most of your field at some point -- and he got a kick out of my agog state.

SfN 2010: Monday

Monday morning's highlight was the Experience-Dependent Synaptic Plasticity and Neurogenesis in the Degenerating and Injured Brain nanosymposia session.


Carl Cotman, professor of neurology at UC Irvine and a potential mentor, spoke about the effects of exercise in mice, canines and humans.  Dr. Cotman specializes in Alzheimer's (AD) research, and presented a collection of studies highlighting the effect of exercise on blood flow, amyloid aggregation and instance of BDNF.  In transgenic mouse models of AD (Tg2576), Cotman discussed reduced amyloid and increased BDNF with exercise.  In humans with AD, increased vessel volume and blood flow was observed with fast walking, corroborative with decreased amyloid reported by Liang et al in the Annals of Neurology this year.


Most notably, Dr. Cotman proposed that the brain "has a memory for exercise."  Exemplifying this statement was his study from 2005 where AD rats exercised on a treadmill for one week, resulting in increased BDNF in the hippocampus.  Some of these rats proceeded without exercise in the following week which resulted in decreased BDNF levels.   These levels increased rapidly when the animals were exercised for an additional week to levels beyond those revealed due to the initial exposure, a phenomenon that typically takes weeks to induce in naive rats.  This "memory for exercise" may prove to be key in designing rehabilitative exercise programs.


Mike Jakowec and Giselle Petzinger, respectively professor and clinician-researcher at USC, represented the recent work of their labs as well as the strong collaborative efforts within USC's Neuroscience labs.  Advocate of exercise in rodent models of Parkinson's disease, Dr. Petzinger presented evidence that exercise may be working through the indirect dopamine pathway (D2) to aide motor recovery.  Mot strikingly to me, their lab has reported that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) results in dopamine neuron spine loss specific to the D2 pathway via [F]Fallypride radiotracing (PET scan).  Exercise in their MPTP mouse model results in a 98% increase in the striatal D2 receptor.  This research suggests some very interesting targets for intervention.


The David Kopf lecture on Neuroethics was given this year by Hank Greely, professor of law at Stanford, and a professor by courtesy of genetics at the School of Medicine.  Beyond delivering a lecture as eloquently as one will ever hear, the poignant stars of Dr. Greely's talk were copious.


Dr. Greely opened by saying that the "ethical issues of neuroscience are 10 years behind those in genetics," referring to the paradigm sweeps that genetic discoveries have prompted (i.e. eugenics).  He elaborated that the implications of neuroscientific discovery were "more important than [those of] genetics, made so by immediacy and power."  Namely, neurological dysfunction has very present consequences, whereas genetic abnormalities must emerge on the physiological level before they can be acted upon.  For instance, if you were to find yourself predisposed to Alzheimer's through genetic testing, you would be protected from discrimination by the Genetic Information Non-discrimination Act of 2008.  However, there exists no such protection if you are diagnosed via MRI.


Humans as mind-readers, MRI's distinguishing between conscious and unconscious vegetative states, and the responsibility of humanity to discern what is an adverse disease and what is just a condition that makes "us" (the indirectly affected "us") uncomfortable:  these are some of many issues with which neuroscientists can become dangerously dissociated, but the bench does not separate us from the issues produced by our discoveries.  The mindfulness of scientists guides social consequences.


I refer readers to Stanford's Neuroblog and The Neuro Dilettante for more adequate coverage of Greely's lecture.



Liang KY, Mintun MA, Fagan AM, Goate AM, Bugg JM, Holtzman DM, Morris JC, & Head D (2010). Exercise and Alzheimer's disease biomarkers in cognitively normal older adults. Annals of neurology, 68 (3), 311-8 PMID: 20818789


Adlard, P. (2005). Voluntary Exercise Decreases Amyloid Load in a Transgenic Model of Alzheimer's Disease Journal of Neuroscience, 25 (17), 4217-4221 DOI: 10.1523/JNEUROSCI.0496-05.2005

SfN 2010: Sunday

Before I extrapolate on neuroscientific happenings, I must take this opportunity to reflect on how stellar it is that I am staying on a docked yacht, and drinking margaritas at sunset on the deck of said yacht with two extraordinary people.

Onward.

Sunday was booked with two four-hour poster sessions and one afternoon symposium.  The morning was filled with Spinal Cord Injury and Parkinson's Therapies sessions, with a not-so-quick diversion to the triple-letter aisles where one of my prospective graduate program PIs sported sixteen -- count 'em, sixteen -- posters on expression of the immediate early gene Arc in various brain regions associated with cognition in models of aging and environmental stimulation (Session 204. Learning and Memory: Genes and Aging).

The afternoon's symposium of choice was Silvia Arber's talk on Motor Circuits, which was excellent but for a somewhat misleading in title.  This particular neuroscientist sees "Connecting Motor Circuits" and expects a comprehensive discussion of relationships of both central and peripheral nervous system motor circuits.  Instead, Dr. Arber focused on her research, which is entirely peripheral and has become famous for classifying the proprioceptive identity of the spinal cord; specifically, the innervation of the dorsal and ventral horns, and during what movements their respective peripheral pathways are activated.  Numerous beautifully conducted studies were exemplified during her talk.

An afternoon of inducing, protecting against and ameliorating dyskinesias brought me back to my element, but my brain was re-tuned once more with a quick tour through the vendor exhibits.  The vendors first open shop on Sunday, and traffic through their booths was daunting.  Free widgets, pens and t-shirts galore spanned the entire length of the convention center; I am told that there were significantly more vendors this year than ever before.

Adorned with newly acquired tote bags full of free scincey goodies, off we went to the The Fish Market on Harbor Drive to pick up some prawns to accompany our margaritas -- peeled, cooked and devoured on our boat.

SfN 2010: Saturday

Glenn Close has been a heroine of mine since 1991, when I saw her in Sarah Plain and Tall.  Today, I met her... almost.

Glenn Close, her sister Jessie Close and nephew Calen Pick were the introduction to my first SfN.  Their stories of battling bipolar disorder and schizoaffective disorder were strong, and deeply touching.  Bringchange2mind.org has done a fantastic job of reaching out to people with or touched by mental illness; and communicating to the world that mental illness is a physical ailment like any other of the body, not to be isolated as demonic or self-inflicted.  Calen spoke of the self-hatred coincident with not being able to control your own stream of consciousness or emotion, and the effort that bringchange2mind puts toward erasing this attitude from Consumers, survivors and loved ones whose lives are impacted.  One in four families is touched by mental illness, Glenn reminded us.

Jessie and Calen gave very personal insight into their struggles to find and hold on to reality, and opened a week-long convention of cutting edge research by suggesting that neuroscientists like those present were responsible for their current states of health.  It is so infrequently in science that people look at your work and say, "this is so beautiful, what you've done."  And it was profoundly impactful to me to hear Calen Pick thank the present body of researchers for their work.  From an artist, that is an especially beautiful complement.

The afternoon's first poster session was overwhelming only in that I did not expect to be pumping so much adrenaline.  Twenty-six posters interrupted by a nanosymposium was a good pace.  However, my session frequency was all over the place, and I spanned the length of the convention center from the single to the triple letter aisles more than once.  The following days were much more focused.

Nearing 5pm, as I walked out of the center I passed Glenn and Jessie Close and Calen Pick in the company of their entourage.  In the ten seconds during which I approached and then passed them by, I made eye contact, smiled and nodded respectfully, chickened out of approaching and asking to shake the hand of my emotive activist childhood heroine, and regretted it.  Thus began the epicness of my first SfN. 

Society for Neuroscience, 2010: An Introduction

The next several posts will be SfN-centric, as it is my first year of both attending and presenting and I am teeming with fledgling excitement.  So that I am not undone by the insidious and unrealistic lure to see and do everything, I have been following the guidance of a few Neurobloggers and of my boss.

After going through the almost innumerable legions of posters and symposia in the Meeting Planner by session, then doing separate name and keyword searches, I realized that getting the most out of every one of the many hundreds of titles I had ear marked was just not realistic.  Though I have not slimmed down my itinerary, I have taken the sage advice of The Neuro Dilettante, and acknowledged that even if I visit all the posters on my itinerary, I will have only seen a minute fraction of what this mass international gathering has to offer, and that is fine.

I am told that many first-timers (mostly grad students) burn out within the first two days attempting to see and learn about everything.  In the interest of surviving the entire week, I will not be rushing about with my laptop or busily scratching volumes of notes.  Instead, the most key research conclusions or methodology along with contact information will be incorporated into my notepad.  And if I happen to spend a little extra time at the posters presented by the PI's with whom I'm interested in doing my PhD work (in two years, universe willing)... so be it.

And I intend to exploit the free give-aways of the vendors who have taken the time to email me with specific requests for demonstration and face time.  Can one have too many key chain laser pointers or letter openers? 

I will also be equipped with thumb tacks, mini-poster hand-outs, sharpies, bottled water, a sweater (yes, though San Diego will be between 70-80 degrees the convention center is kept at a chill), and convention center floor plans.

Following the high of seeing Glen Close, heroine of my childhood, on Saturday afternoon, the Navigating the Meeting seminar may be just the thing to settle me into conference mode -- I highly recommend this tool, especially for those who do not yet have plans of attack.  I intend to be a SfN Ninja by the end of this.

On Choosing a Publishing Name: Part Deux

When the proofs of my first publication were forthcoming and reaching decision became pressing, choosing my publishing name was not nearly so convoluted as I had built it up to be.

Though my maiden name is as unique as they come, my husband is a huge part of my work and why I am able to create what I do.  His last name is the one with which I have decided to publish, and my maiden name will be assembled in an unmistakable set of initials.  This representation, I have decided, adequately honors all in my family while keeping my title reasonably concise and fairly recognizable while avoiding the logistical nightmare of separating legal and publishing names.

On Choosing a Publishing Name

I decided in high school, after finally getting my signature to a state of calligraphic excellence, that it was a sign this name was truly mine and I would never lose my last name.

However, as a huge fan of historical record keeping and genealogical efficiency, and out of solidarity with my very-soon-to-be husband, I would like to have his last name as well.

I am now faced with imminent marriage and the simultaneous publishing of my first science journal article, and must decide how I will define myself professionally.  This decision has seen weeks of emotional turmoil though the obvious solution, simple and logical, took a while to sit right.

As a research scientist, I want to be identifiable and easily associated with my work.  My maiden name is so Ellis Island-unique that there is not another soul on earth who has it to whom I am not related.  I would like to continue being affiliated with my clan (read: my clan is notoriously and hazardously crazy, and it is not so much the affiliation to them as to my father, and to honor my parents, that is a strong need).  My fiance's last name is strong, but ever-so-common.

This is the obvious and logical decision:

Legally: Maiden HisLast
Socially: HisLast
Professionally: Maiden

My point of contention has been whether or not to use both of our names in publications.  If my pen name is solely my maiden name, I am ignoring his profound role in my accomplishments (read: without such support and enthusiasm for my own ambition and ardor, my productivity would certainly be less colorful).  However, if I use both of our names professionally, the uniqueness of my maiden name is countered by the addition of his common one.

Does it make a name less strong to have two parts?  In terms of identity, I don't think so.  But in terms of a pen name, it does help them to compliment one another: our last names do not compliment one another.  This clash is the caveat.  Perhaps it is mostly because I am new to the idea, or perhaps it is because (as an amateur script editor for a film maker) I know that a character's name is strongest and most memorable when it does not trail on being degraded by mumbling as a telomere by replication.

Ultimately, the name is mine and if at least part of it is memorable in publication, then I am satisfied.  And if we have children along the line, they will take his name, because history has enough obstacles to accuracy without having to negotiate when names were anagramed, traded or ultra-hyphenated.   Therefore:

Legally: Maiden HisLast
Socially: HisLast
Professionally: Maiden HisLast

However!

At this point in the rationale, the fiance himself finally feels it appropriate to chime in again.  His original wish was that I take his name.  However, his evolved stance is that anyone who knows me well enough on a social/personal level for me to care will know me as Mrs HisLast or Dr Maiden.  Therefore, rather than have my pen name be Maiden HisLast, he votes for the original scenario of a solitary, solid last professional name.  Therefore, the final consensus is:

Legally: Maiden HisLast
Socially: HisLast
Professionally: Maiden

Journal Club Follow-Up: Coenzyme Q10

Many Parkinson's patients take Coenzyme Q10 supplements.  As mentioned in the previous post, CoQ10 is part of the Electron Transport Chain -- a very important part, in fact, as it alleviates pressure on our precarious and susceptible-to-aging Complex I.

While many theorize that Complex I is shut down or is deficient in PD (1, 2, 3, 4), others believe that deficient activity of the CoQ10 pool beside Complex I is more to blame (5, 6).  The CoQ10 theory claims that PD causes a deficiency in the CoQ10 pool that carries electrons from Complex I to their next destination without producing ROS.  As a result of low CoQ10, electrons build up in Complex I and get released from the entrance because they cannot leave through the exit.

Some PD patients are able to take CoQ10 supplements and improve their condition (7).

It is my opinion that CoQ10 is a palliative treatment and not a long-term solution.  The Ndi1gene therapy discussed in the previous post is a better option if it makes it to, and proves robust in clinical trials.  My reasoning is that a genetic replacement for Complex I is a more stable therapy than a persistent aid to CoQ10: it is more permanent and a more widespread solution; a large portion of PD patients do not have CoQ10 deficiencies.  Ndi1 would also contribute to the sustaining of the proton gradient in the mitochondria, also vital to creating energy in the ETC.


Greenamyre, J. (2001). Response: Parkinson's disease, pesticides and mitochondrial dysfunction Trends in Neurosciences, 24 (5) DOI: 10.1016/S0166-2236(00)01788-4

Schapira AH (1994). Evidence for mitochondrial dysfunction in Parkinson's disease--a critical appraisal. Movement disorders : official journal of the Movement Disorder Society, 9 (2), 125-38 PMID: 8196673

Morais, V., Verstreken, P., Roethig, A., Smet, J., Snellinx, A., Vanbrabant, M., Haddad, D., Frezza, C., Mandemakers, W., Vogt-Weisenhorn, D., Van Coster, R., Wurst, W., Scorrano, L., & De Strooper, B. (2009). Parkinson's disease mutations in PINK1 result in decreased Complex I activity and deficient synaptic function EMBO Molecular Medicine, 1 (2), 99-111 DOI: 10.1002/emmm.200900006

Storch, A., Jost, W., Vieregge, P., Spiegel, J., Greulich, W., Durner, J., Muller, T., Kupsch, A., Henningsen, H., Oertel, W., Fuchs, G., Kuhn, W., Niklowitz, P., Koch, R., Herting, B., Reichmann, H., & , . (2007). Randomized, Double-blind, Placebo-Controlled Trial on Symptomatic Effects of Coenzyme Q10 in Parkinson Disease Archives of Neurology, 64 (7), 938-944 DOI: 10.1001/archneur.64.7.nct60005

Journal Club: Neuroprotection by NGI1 Gene in a Parkinson's Disease Model

One of the most popular mechanisms of pathology in Parkinson's disease (PD) research is cell death through Complex I inhibition in the mitochondria.

Mitochondria -- affectionately known as the power houses of all cells -- are where energy is produced.  There is a series of protein complexes forming the Electron Transport Chain (ETC) which, as their acronym exposes, steal electrons from contributing molecules and convert them into energy and water.

The fully reduced H2O form of oxygen is non-toxic.  The various single-electron intermediates between O2 and H2O are ALL toxic free radicals, the so-called Reactive Oxygen Species (ROS).  Complex IV (cytochrome oxidase complex) has a gate that transfers electrons directly to O2, reducing it to water without generating ROS.  Complexes I and III, however, occasionally allow electrons to escape from the ETC to form ROS.

In Parkinson's disease, Complex I is dysfunctional, and it is thought that much higher concentrations of ROS are produced in the ETC.  These attack multiple systems in the mitochondria which eventually lead to the breakdown of cellular DNA, and the cell itself.

Many cases of PD are characterized post mortem by a selective loss of dopamine cells via this mechanism.

The study by Marella et al has used the variant of Complex 1 found in yeast to attempt to quell this rampant ROS formation.  Using the rotenone rat model, the group injected the Ndi1 gene via biodegradable microspheres (classy...), and monitored recovery in the substantia nigra pars compacta (SNpc; the primary region of dopamine cell loss) and in behavior.

After 60 days, tissue analysis of Ndi1-injected rotenone rats showed increased staining for viable dopamine cells in the SNpc.  Those lesioned rats who did not receive the Ndi1 gene showed significantly fewer stained dopamine cells, and extensive staining with antibody against 8-oxo-dG (indicating oxidative damage to DNA).

My gripe with the study -- in addition to its not being tremendously written -- is that it is lacking in relevant behavioral assessment.  The study monitored speed of movement, and the number of rotations in a widely used apomorphine test.  The rotations test is normally used in unilaterally lesioned animals (which these were) to indicate preference to rotate in one direction.  However, the direction of rotation induced by apomorphine in this study was determined by more factors than the unilateral lesion, which caused the animals to rotate in both directions.  Therefore, behavioral data was reported as the "number of animals exhibiting 100% lateralized rotation irrespective of the direction."  In my opinion, the behavioral test was severely weakened by this caveat and the group should have employed a quick additional test... like the Whisker test or lateralized grip strength.

This suggests that the Ndi1 gene -- the yeast version of Complex 1 -- was able to compensate for inhibition of Complex 1 by rotenone, decrease ROS activity by serving as an electron transporter, and lessen cell death.  If this could be replicated in higher animals, it may prove a viable candidate for clinical trials. 

Aside from deficits in writing and behavioral analysis, the story told by this article was fascinating with  very intriguing implications.   They did their homework, publishing several studies on in vitro activity of the Ndi1 gene and subsequent protein (1, 2) as well as confirming benign effects of introducing a yeast gene in vivo (1, 2)  .

Marella M, Seo BB, Nakamaru-Ogiso E, Greenamyre JT, Matsuno-Yagi A, & Yagi T (2008). Protection by the NDI1 gene against neurodegeneration in a rotenone rat model of Parkinson's disease. PloS one, 3 (1) PMID: 18197244

Journal Club: RBD and Parkinson's Disease

There is a great deal of research being done regarding the mechanisms of Parkinson's disease (PD) and possible targets for therapeutic cures.  Yet, it is one of many conditions that remains incredibly hard to diagnose.  PD patients are not typically diagnosed until the disease has progressed to 70-90% dopamine cell depletion when symptoms become observable in movement behaviors (Jankovic 2008).

By the time cell loss has progressed this far, it is very difficult to achieve a successful long-term treatment plan.  Pharmaceuticals such as L-Dopa (Jubalt et al 2009) and rasagiline (Olanow et al 2009) are generally effective, but can lose their effect or cause dangerous side effects over time.  Deep brain stimulation has been shown to be very effective behaviorally, but there it is an intense procedure which has occasionally been correlated with subsequent cognitive impairments (York et al 2008).  Exercise therapies have also shown promise in recovery therapy, but have seemed more lasting in the peripheral nervous system than the dopamine system of the CNS (Goodwin et al 2009; Petzinger et al 2007; Muhlack et al 2007).

When it is so important to try to identify markers of PD before it progresses beyond our current ability to treat it in a lasting way, Dr. Ronald Postuma and colleagues out of Montreal, Quebec, Canada have identified REM sleep behavior disorder (RBD) as a possible indication of developing PD.  RBD is the loss of muscle atonia that normally occurs during REM sleep, causing a person to thrash unconsciously.

Their study is a beautiful longitudinal representation of several patients diagnosed with RBD in the 1980s who developed either PD or dementia by 2004.  Of their 17 final RBD patients, 6 (5m/1f) had developed PD and 11 (10m/1f) developed dementia.

The Postuma group suggests that there might be a discrete pathological condition specific to "RBD-then-neurodegeneration"which has different early manifestations than PD alone.  A very interesting concept as RBD, dementia and PD are all distinctive in their Lewy body and ß-amyloid
deposition.  If further study of the evolution of RBD into PD shows a strong correlation, this could be a giant leap forward in terms of PD diagnosis and early treatment.  There may indeed be a distinct pathology to this progression or there may not be.  In any case, this is a very important study in the field of neurodegenerative disorders, and I believe it is expecially important to get longitudinal studies like this one funded.

The staging model of PD developmnt proposed by Braak et al in 2003 proposes that the effects of PD begin in the olfactory area of the brain, spreading to autonomic and sleep-involved regions, and finally to dopamine loss in the nigrostriatal pathway and several downstream cortical pathways (Braak et al 2003).  The Braak model, in conjunction with this new proposal from Postuma et al, leaves me wondering about Restless Leg Syndrome (RLS) as another possible indicator of PD.

The connection between RLS and PD is in dopaminergic transmission, as suggested by Dr. David Rye in 2004.  A study by Tan et al in 2002 found that prevalence of RLS in PD patients was not significantly different from incidence in their healthy population, roughly 15%.  The Tan study was not looking at progression of RLS into PD, however, so it is possible, as suggested in the Postuma study, that RLS-PD may have its own unique pathology. 

To date, I have not found any longitudinal studies of RLS progressing into RBD or PD.