Niemann-Pick's and Gaucher's diseases.

A short account is presented of the evolution of knowledge concerning Niemann-Pick's and Gaucher's diseases, two autosomal recessive genetic disturbances of lysosomal storage function. This culminated in the intriguing realisation, arising from mounting clinical and molecular evidence, that glucocerebrosidase mutations constitute the most common risk factor for Parkinson's disease identified to date.

Erich Harnack (1852-1915) and a short history of apomorphine.

Apomorphine, now established as an efficacious therapy for refractory motor fluctuations in levodopa-treated Parkinson's disease, has a long and chequered history in medical and veterinary therapeutics. The preclinical in vivo pharmacological effects of apomorphine were first studied about 150 years ago following which the drug was introduced for the treatment of behavioural vices in domesticated animals. Erich Harnack's early pharmacological studies in Dorpat (now Tartu, Estonia), where he belonged to the pharmacological dynasty of Buchheim and Schmiedeberg, are of particular historical significance as he emphasised that while apomorphine had potent emetic effects, the drug also had complex effects on the central nervous system.

Genetics and the neurodegenerations: musings of a gadfly.

An elderly perplexed clinician who has lived through the molecular revolution briefly considers the potential of genetics in elucidating the causes of neurodegenerations and expresses certain reservations.

Why catechol?

A brief history of the evolution of the term catechol amine and relationship to the treatment of Parkinson's disease.

The differentiation potential of human foetal neuronal progenitor cells in vitro.

Previously, this laboratory has shown that human foetal progenitor cells derived from ventral mesencephalon (VM) can be developmentally directed towards a dopaminergic lineage. In the present study, the effects are reported of several as yet untested differentiation/survival factors on the controlled conversion of neural progenitor cells to dopaminergic neurons. Positive immunoreactivity to tyrosine hydroxylase (TH) and raised levels of dopamine (DA) and its metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC), secreted into culture medium, were used to indicate the presence of the dopaminergic neuronal phenotype, i.e., active TH. Incubation with retinoic acid (RA) (0.5 microM) lead to an increase in the number of cultured cells showing positive immunoreactivity for the neuronal marker, microtubule-associated protein (MAP)-2ab. A concomitant increase in TH-positive immunoreactivity was also demonstrated. The brain-derived neurotrophic factor (BDNF) (50 ng/ml), glial-derived neurotrophic factor (GDNF) (10 ng/ml) and interleukin-1 beta (IL-1 beta) (10 ng/ml) also had positive effects in promoting neural progenitor cell differentiation towards the dopaminergic phenotype in the presence of dopamine (10 microM) and forskolin (Fsk) (10 microM). There was no synergy in this effect when progenitor cells were incubated with all of these agents simultaneously. The trans-differentiation potential of the progenitor cells to be directed towards other neurotransmitter phenotypic lineages was also investigated. It was found that, with the right cocktails of agents, serotonin (Ser) (75 microM), acidic fibroblast growth factor (aFGF) (10 ng/ml), BDNF (50 ng/ml) and forskolin (10 microM), these same cells could be directed down the serotonergic cell lineage pathway (as judged by the appearance of tryptophan hydroxylase (TPH) positive immunoreactivity, and synthesis of 5-HT and its metabolites, secreted into the culture medium). However, no cocktail containing noradrenaline (10 nM-500 microM), BDNF (50 ng/ml) and forskolin (10 microM) was found which promoted differentiation towards the noradrenergic cell phenotype as judged by the absence of any TH or D beta H positive immunoreactivity, and no formation of 3,4-dihydroxyphenylethyleneglycol (DOPEG), the principal metabolite of noradrenaline. The controlled trans-differentiation potential of these cell could pave the way for development and harvesting of large numbers of neurons of the appropriate neurotransmitter phenotype for future transplantation therapies for the treatment of neurodegenerative diseases such as Parkinson's disease (PD) and Alzheimer's disease.

The controlled conversion of human neural progenitor cells derived from foetal ventral mesencephalon into dopaminergic neurons in vitro.

The expansion and differentiation of neural progenitor cells in vitro provides an approach to study the development and differentiation of neurons. The ventral mesencephalic area of the brain is an important source of neural progenitor cells and the differentiated neural progenitor cell has paramount potential for use in transplant therapies such as those used in the treatment of neurodegenerative diseases. Here, the controlled conversion of human foetal progenitor cells derived from ventral mesencephalon into dopaminergic neurons is reported. The immunoreactivity to tyrosine hydroxylase (TH) and levels of dopamine (DA) and its metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC), secreted into culture medium, were used to assess dopaminergic neuronal phenotype. Expansion of the neural progenitor cells for 3 weeks in the presence of basic fibroblast growth factor (2 ng/ml) followed by its withdrawal resulted in approximately 60% of cells staining positive for TH, when challenged in concert with brain-derived neurotrophic factor (50 ng/ml), DA (10 microM) and forskolin (10 microM) for a further 3 weeks. A corresponding 41-fold increase in DA and DOPAC was measured in the incubation medium by HPLC. Therefore, the successful conversion of human foetal progenitor cells in vitro resulting in the desired dopaminergic neuronal phenotype, could provide a solution to the problem of limited availability of human foetuses for clinical surgical transplantation therapies, which are currently in progress for the treatment of neurodegenerative diseases such as Parkinson's disease.