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558 http://neurology.thelancet.com Vol 5 July 2006

US researchers have identifi ed the mechanism by which damage to cells by free radicals leads to the accumulation of misfolded proteins reported in neurodegenerative disorders, such as Parkinson’s and Alzheimer’s diseases.

The link is the chaperone protein protein disulphide isomerase (PDI), which is present in the endoplasmic reticulum.

Under normal circumstances PDI is responsible for maturation and transport of unfolded proteins, and helps to rearrange the bonds in misfolded proteins to enable them to function normally.

But through a series of experiments, Stuart Lipton (Center for Neurosciences and Aging and the Burnham Institute, La Jolla, CA, USA) and colleagues found that nitric oxide (NO), a free radical present in raised amounts in neurodegenerative

disorders, attacks PDI, altering its structure.

The researchers then found that altered PDI is present in the brains of people with Parkinson’s and Alzheimer’s diseases but not in those of unaff ected controls (Nature 2006; 441: 513–17). With a cell model of neurodegeneration, the team found that S-nitrosylation of PDI disables its function and enables the accumulation of polyubiquitinated proteins, which contribute to cell death.

Lipton said the fi ndings open the way for new treatments and the presence of S-nitrosylated PDI could be a potential disease marker.

“Our data demonstrate a previously unrecognised relationship between NO and protein misfolding in degenerative disorders, showing that PDI can be a target of NO in cellular models of Parkinson’s disease and human neurodegenerative disease.”

He added: “Most importantly, [the altered protein] can be seen in the absence of a genetic mutation”. This fi nding may help to explain why disease in families with genetic mutations that cause Parkinson’s or Alzheimer’s diseases is the same as the disease in sporadic cases—in these patients NO attacks the protein folding machinery, thus making proteins misfold in the same way that a mutation in a gene encoding a protein might.

Fred Cohen (Department of Cellular and Molecular Pharmacology at the University of California, San

Francisco, USA) said that until now molecular links between free radicals and protein misfolding had proven elusive. “Over the past 10 years, it has become increasingly clear that many neurodegenerative diseases are diseases of protein misfolding. The work by Lipton and colleagues provides molecular detail for a target of free radical damage.”

But he added that there were questions to answer: “If we had specifi c pharmacological ways to reactivate PDI and those agents crossed the blood–brain barrier, then there are some immediate experiments to try in mouse models of these disorders. However, it is not clear what level of activity would be necessary to reverse or even stall disease progression. It is also not clear that once protein misfolding starts, that the process can be reversed.”

José Barral (Department of Neuroscience and Cell Biology, University of Texas Medical School, Houston, TX, USA) agreed the fi ndings had very practical implications. “Now that an actual enzymatic activity has been identifi ed as involved in the neurodegenerative process of these diseases, small molecule inhibitors that prevent the inactivation of PDI could be designed or screened for. Additionally, assays to detect PDI S-nitrosylation could perhaps be developed to screen for a wide array of neurodegenerative diseases before the onset of overt symptoms.”

Emma Wilkinson

Link identifi ed between free radicals and protein misfolding

PDI regulates protein folding in the endoplasmic reticulum

Cholesterol stops medulloblastoma growthA new study suggests that cholesterol may have a critical role in medulloblastoma growth. Ryan Corcoran and Matthew Scott (Stanford University School of Medicine, CA, USA) investigated how cholesterol and its derivatives aff ected

the growth of medulloblastoma cells in culture.

Medulloblastoma is the most common malignant brain tumour and most typically occurs during childhood, with an estimated incidence of 11 000 children aff ected worldwide every year.

The tumour is incurable in about a third of patients and treatment options are limited. Signal transduction of the protein Sonic hedgehog (Shh) is critical in medulloblastoma growth. Sterol synthesis, in turn, is required for Shh signal transduction and

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http://neurology.thelancet.com Vol 5 July 2006 559

medulloblastoma growth. Previous studies showed that impairment of sterol synthesis blocks Shh signal transduction; however, the mechanism of this is unknown, and the products of sterol synthesis that are necessary for Shh signal transduction are unknown. In their study, Corcoran and Scott looked at sterol synthesis in medulloblastoma cells and reported that cholesterol, in particular, is involved in Shh signal transduction in medulloblastoma cells (Proc Natl Acad Sci USA 2006; 103: 8408–13).

The researchers fi rst investigated whether sterol-synthesis inhibitors reduce Shh target gene transcription in medulloblastoma cells and

whether these inhibitors block Shh pathway-dependent proliferation. They also showed that the eff ects of sterol synthesis inhibitors could be reversed by exogenous cholesterol or a cholesterol derivative, oxysterol, proving that cholesterol and oxysterol have critical roles in the Shh signal-transduction pathway in medulloblastoma cells. The investigators also report that certain oxysterols can maximally activate Shh target gene expression through the Smoothened (Smo) protein as eff ectively as the Smo full agonist, SAG.

Corcoran and Scott’s study suggests possible applications for sterol-

synthetic-pathway inhibitors in Shh pathway-derived tumours such as medulloblastomas—opening up new potential therapeutic avenues. Their study also found that sterol synthetic pathway inhibitors together with the Shh pathway antagonist, cyclopamine, combined more eff ectively to block Shh target gene transcription and medulloblastoma proliferation.

“Concurrent blockade of sterol synthesis may enhance eff ects of Smo antagonists, which are currently under clinical development for treatment of Shh pathway-dependent tumors”, the authors suggest.

Nayanah Siva

A mouse model of autism? Researchers at the University of Texas Southwestern Medical Center (TX, USA) have generated a transgenic mouse lacking Pten—a tumour suppressor gene—that shows behaviour typical of autism spectrum disorder (ASD). “We deleted Pten in limited diff erentiated neuronal populations in the cerebral cortex and hippocampus of mice”, the authors write (Neuron 2006; 50: 377–88). “Resulting mutant mice showed abnormal social interaction and exaggerated responses to sensory stimuli”.

“Numerous studies have demonstrated a genetic contribution to development of the autistic phenotype”, write Joy Greer and Anthony Wynshaw-Boris in an accompanying Preview article (Neuron 2006; 50: 343–45). “However, a neuropathological cause of ASD remains elusive, although varied anatomical and cellular changes have been reported in brains from ASD patients.”

Chang-Hyuk Kwon and co-workers used a targeted promoter to knock out Pten expression in discrete neuronal populations in the cerebral cortex and hippocampus. The researchers report several resulting morphological changes in the brains of the mutant

mice: progressive macrocephaly of the forebrain; increased soma size of neurons lacking Pten; enlargement of the mossy-fi bre tract in the dentate gyrus; dendritic hypertrophy; and an increase in dendritic spine density.

The researchers went on to investigate intracellular signalling in the mutant mice. Pten is a lipid phosphatase that inhibits phosphatidylinositol 3-kinase (PI3K) signalling. They found increased phosphorylation of AKT, a target of PI3K, in hypertrophic neurons of the dentate gyrus.

Coupled with these morphological and signalling changes, Kwon and co-workers saw changes in social behaviour in mice lacking Pten. The mutant mice were less interested in interacting with a new mouse, exhibiting less sniffi ng and approaching behaviour than normal control mice, and showed no preference over a cage containing a companion mouse to an empty cage. The researchers also noticed that the mutant mice were more resistant to handling and were hyperactive in stressful situations. To investigate this further, they tested the mutant mice in standard anxiety tests—such as the

open fi eld test and the elevated plus maze—and found some increases in anxiety-like behaviour.

“Our data suggest that the abnormal activation of the PI3K/Akt pathway in specifi c neuronal populations can underlie macrocephaly and behavioural abnormalities reminiscent of certain feature of human ASD”, the authors conclude. However, “there are aspects of ASD that are not recapitulated in the Pten mutants”, caution Greer and Wynshaw-Boris.

Rebecca Love

Gene controlling interaction in mice provides clue to autism

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