The future of cell therapies and brain repair: Parkinson's disease leads the way.

During the past 40 years brain tissue grafting techniques have been used both to study fundamental neurobiological questions and to treat neurological diseases. Motor symptoms of Parkinson's disease are largely due to degeneration of midbrain dopamine neurones. Because the nigrostriatal pathology is relatively focused anatomically, Parkinson's disease is considered the ideal candidate for brain repair by neural grafting and dopamine neurone transplantation for it has led the way in the neural transplantation research field. In this mini-review, we briefly highlight four important areas of development. First, we describe marked functional benefits up to 18 years after transplantation surgery in patients with Parkinson's disease. This is proof-of-principle that, using optimal techniques and patient selection, grafted dopamine neurones can work in humans and the duration of the benefit exceeds placebo effects associated with surgery. Second, we describe that eventually protein aggregates containing α-synuclein, identical to Lewy bodies, develop inside foetal dopamine neurones transplanted to patients with Parkinson's disease. This gives clues about pathogenetic mechanisms operating in Parkinson's disease, and also raises the question whether neural graft function will eventually decline as the result of the disease process. Third, we describe new emerging sources of transplantable dopamine neurones derived from pluripotent stem cells or reprogrammed adult somatic cells. Fourth, we highlight an important European Union-funded multicentre clinical trial involving transplantation of foetal dopamine neurones in Parkinson's disease. We describe the design of this ongoing trial and how it can impact on the overall future of cell therapy in Parkinson's disease.

IGF-1 protects against diabetic features in an in vivo model of Huntington's disease.

Huntington's disease (HD) is the most prevalent polyglutamine expansion disorder. HD is caused by an expansion of CAG triplet in the huntingtin (HTT) gene, associated with striatal and cortical neuronal loss. Central and peripheral metabolic abnormalities and altered insulin-like growth factor-1 (IGF-1) levels have been described in HD. Thus, we hypothesized that restoration of IGF-1-mediated signaling pathways could rescue R6/2 mice from metabolic stress and behavioral changes induced by polyglutamine expansion. We analyzed the in vivo effect of continuous peripheral IGF-1 administration on diabetic parameters, body weight and motor behavior in the hemizygous R6/2 mouse model of HD. We used 9 week-old and age-matched wild-type mice, subjected to continuously infused recombinant IGF-I or vehicle, for 14 days. IGF-1 treatment prevented the age-related decrease in body weight in R6/2 mice. Although blood glucose levels were higher in R6/2 mice, they did not reach a diabetic state. Even though, IGF-1 ameliorated poor glycemic control in HD mice. This seemed to be associated with a decrease in blood insulin levels in R6/2 mice, which was increased following IGF-1 infusion. Similarly, blood IGF-1 levels decreased during aging in both wild-type and R6/2 mice, being significantly improved upon its continuous infusion. Although no significant differences were found in motor function in R6/2-treated mice, IGF-1 treatment highly improved paw clasping scores. In summary, these results suggest that IGF-1 has a protective role against HD-associated impaired glucose tolerance, by enhancing blood insulin levels.

Early detection of age-related memory deficits in individual mice.

To date, no consensus has been reached concerning the age of the earliest onset of age-related cognitive deficits in rodents. Our aim was to develop a behavioral model allowing early and individual detection of age-related cognitive impairments. We tested young (3 months), middle-aged (10 months) and aged (17 months) C57Bl/6 mice in the starmaze, a task allowing precise analysis of the search pattern of mice via standardized calculation of two navigation indices. We performed mouse-per-mouse analyses and compared each mouse's performance to a threshold based on young mice's performances. Using this method we identified impaired mice from the age of 10 months old. Their deficits were independent of any sensorimotor dysfunctions and were associated with an alteration of the maintenance of the hippocampal CA1 late-LTP. This study develops reliable methodology for early detection of age-related memory disorders and provides evidence that memory can decline in some individuals as early as from the age of 10 months.