Gene Discovery In Neurodegenerative Diseases

National Institute Of Mental Health

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Abstract

We have performed discrete dissection of the substantia nigra of the human Parkinson and control brain and have isolated an interesting protein by differential display. This gene was up regulated in the Parkinson brain compared to the normal brain. This protein, known as flotillin-1 was discovered relatively recently. A commercial antibody has become available. We have been carrying out immunohistochemical studies on the rat brain. We have made the very interesting observation that flotillin-1 is diffusively present in the cytoplasm of all dopamine-containing cell bodies. Most prominently the substantia nigra (compacta) and ventral tegmental area (VTA-A10) was revealed by fluorescence microscopy. In addition, A11, A12 (arcuate cell bodies), A13, A14, and A15 cells were revealed to contain flotillin-1. These cells also colocalized with tyrosine-hydroxylase, a catecholamine cell marker. Furthermore, the striatum had a dense localization of flotillin ?containing varicosities. Also observed were a small number of large distorted intense fluorescent varicose fragments suggestive of degeneration of dopamine/flotillin containing fibers. In conclusion, (1) flotillin-1 is diffusively present in the cytoplasm of all dopamine-containing neurons (A8-A15) of the brain supported by colocalization of tyrosine hydroxylase, (2) the striatum contains an abundant localization of flotillin fibers revealing a nigrostriatal dopaminergic system, (3) distorted axons in the striatum are reminiscent of degenerating axonal-terminal dopaminergic nerves which may reflect an aging process, (4) the up-regulation of the flotillin gene of the human Parkinson substantia nigra-containing dopamine cells suggests an increase in the flotillin content of the remaining dopaminergic neurons. The significance of this is unknown. The involvement of flotillin in Parkinson?s disease remains to be studied.