Thankful For: Scuba Diving with Ka Hahalua (Manta Rays)

Here's a new family video. Includes wife Maryruth, daughter Amanda, and daughter's boyfriend Eric.

Hanau ka Ulua, hanau ka Hahalua i ke kai la holo...

--from Kumulipo, a Hawaiian creation story ballad

Last week, we dove Kona side of the Big Island, near the airport, via a boat tour with Big Island Divers. The water was calm, with very little surge. This makes for ideal manta ray night diving.

*Ulua: Caranx ignobilis

*Hahalua: Manta birostris

New evidence for the pesticide-Parkinson's link

A team of MIT researchers have defined a genetic vulnerability in patients previously defined to be genetically predisposed to Parkinson's, which suggests agricultural pest killers of many types may be environmental triggers for the disease in genetically vulnerable humans.

Persons with mutant forms of the gene coding for the nerve cell protein alpha-synuclein are prone to develop Parkinson disease. In that condition, alpha-synuclein protein clumps in the brain cells that are needed to make dopamine, a brain chemical used as a neurotransmitter. Without enough cells making the dopamine substance, the brain cannot enable and moderate body movement properly, causing symptoms which may include tremors and slowing of body movements.

The researchers showed that exposure to small amounts of the herbicide paraquat, the insecticide rotenone, and the fungicide maneb allowed free radical damage to disrupt function of cloned nerve cells created in cell culture from skin cells of the patients. This damage was prevented by correcting the genetic defect by modifying the cellular DNA.

It seems to me that the link to rotenone (which was previously shown to cause oxidative death of dopaminergic neurons in vitro) is especially important, because rotenone is akin to a large number of other naturally occurring plant toxins. This promotes the environmental toxin theories of causes for Parkinson's, a disease that predates agricultural spraying practices. Maneb is already known to promote a Parkinson's like disease in monkeys. Paraquat was shown to predispose to Parkinson's in an epidemiological study a couple years ago.

One missing piece is whether the findings, in persons with Parkinson's with a particular DNA mutation, will turn out to help explain Parkinson's in those without that mutation.

Go organic, or glove and mask and cover skin before spraying the garden, folks.

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ABSTRACT

Isogenic Human iPSC Parkinson s Model Shows Nitrosative Stress-Induced Dysfunction in MEF2-PGC1± Transcription

Ryan, Scott D.; Dolatabadi, Nima; Chan, Shing Fai; Zhang, Xiaofei; Akhtar, Mohd Waseem; Parker, James; Soldner, Frank; Sunico, Carmen R.; Nagar, Saumya; Talantova, Maria; Lee, Brian; Lopez, Kevin; Nutter, Anthony; Shan, Bing; Molokanova, Elena; Zhang, Yaoyang; Han, Xuemei; Nakamura, Tomohiro; Masliah, Eliezer; Yates, John R.; Nakanishi, Nobuki; Andreyev, Aleksander Y.; Okamoto, Shu-ichi; Jaenisch, Rudolf; Ambasudhan, Rajesh; Lipton, Stuart A.

Cell doi:10.1016/j.cell.2013.11.009

Parkinson s disease (PD) is characterized by loss of A9 dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). An association has been reported between PD and exposure to mitochondrial toxins, including environmental pesticides paraquat, maneb, and rotenone. Here, using a robust, patient-derived stem cell model of PD allowing comparison of A53T ±-synuclein (±-syn) mutant cells and isogenic mutation-corrected controls, we identify mitochondrial toxin-induced perturbations in A53T ±-syn A9 DA neurons (hNs). We report a pathway whereby basal and toxin-induced nitrosative/oxidative stress results in S-nitrosylation of transcription factor MEF2C in A53T hNs compared to corrected controls. This redox reaction inhibits the MEF2C-PGC1± transcriptional network, contributing to mitochondrial dysfunction and apoptotic cell death. Our data provide mechanistic insight into gene-environmental interaction (GxE) in the pathogenesis of PD. Furthermore, using small-molecule high-throughput screening, we identify the MEF2C-PGC1± pathway as a therapeutic target to combat PD. "hiPSC-DA neurons (hNs) with PD mutation (SNCAA53T) manifest nitrosative stress"SNCAA53T or mitochondrial toxins induce S-nitrosylated (SNO)-MEF2C in hNs"S-nitrosylation of MEF2C reduces PGC1± expression and impairs mitochondrial function"Reactivation of MEF2-PGC1± rescues SNCAA53T hNs from nitrosative stress-induced death The ±-synucleinA53T mutation, which causes familial Parkinson s disease, increases reactive nitrogen species in dopaminergic neurons, leading to disruption of the MEF2C-PGC1± transcriptional network, which renders dopaminergic neurons more sensitive to mitochondrial stress.

Aloha Friday: Ku'u Home O Kahalu'u

Jerry Santos and Olomana singing classic Hawaiian slack key folk from the seventies.

New Phrenology on Trial: fMRI and the Law in the News

This from NPR:

"More and more lawyers are arguing that some defendants deserve special consideration because they have brains that are immature or impaired, says Nita Farahany, a professor of law and philosophy at Duke University who has been studying the use of brain science in court. About 5 percent of murder trials now involve some neuroscience, Farahany says. 'There's a steady increase of defendants seeking to introduce neuroscience to try to reduce the extent to which they're responsible or the extent to which they're punished for a crime,' she says. Farahany was a featured speaker at the Society for Neuroscience meeting in San Diego this week. Also featured were several brain scientists who are uncomfortable with the way courts are using brain research."

This article reminds me of a bit of history from 180 years ago.  In 1835 Isaac Ray, a physician who could be called the country's first forensic psychiatrist, examined a juvenile who was on trial for beating and mutilating another boy.  In his defense, Dr. Ray considered and could have used a bit of neurological history:  the boy had a severe head injury as an infant and so may have had brain pathology due to injury.  However, the parents were unwilling to testify as to the injury at the trial, so Dr. Ray used phrenology, then considered in the same epistemic category as other neurosciences of the time.  As published by Ray in the scientific journal Annals of Phrenology in 1835, the boy was found to have large areas of the skull where the "Organ of Destructiveness" was thought to be located. This was felt to undermine the boy's capacity to resist violent behavior. Ray commented that "One of my chief purposes... was accomplished. Phrenology had been mentioned seriously in a Court of Justice, without provoking laughter. "

To the judge on the case's credit, after Ray demurred on whether he was certain the phrenology had an impact on the defendant's actions, the court instructed the jury to not depend upon the expert's phrenology, but to concentrate on whether at the time of the incident the boy was able to tell right from wrong.  (For much more about Dr. Ray's phrenology case, see this source article by Dr. Kenneth Weiss ).

What can we learn from Ray's case story?  First, that new fields in neuroscience are often applied in the law before they are mature, and that this tendency needs to be reined in not only by the judges, but by the scientists.  Otherwise, we risk allowing unwitting academic errors to have far greater ramifications than just languishing unconfirmed in the back stacks of our libraries.  Second, that new theories about causes of behavior may include both genuine and false components (the juvenile's infantile head trauma was at least somewhat relevant, his phrenology wasn't) and only decades of confirmation and disconfirmation are likely to show us which details are which. 

Juries will need discernment, well salted with proper skepticism, communicated to them when such neuroscience defenses are used. Such a relatively neutral stance needs to come from all experts in the cases, not just the side without the pretty brain pictures.