Aberrant mRNA in Parkinsonism: Support for Hypothesis from Studies with Chloramphenicol

Abstract

THE observations that the normally high concentration of dopamine in the substantia nigra is reduced in Parkinsonism¹, that reserpine, which depletes catecholamines, can produce a Parkinsonian syndrome² and that both anticholinergic drugs and L-dopa partially relieve the symptoms of the disease^3,4, have led to the implication of an imbalance between dopaminergic and cholinergic activity in Parkinsonism. Our recent results, however, support previous reports that, apart from a neuro-transmitter deficiency, a dysfunction of protein synthesis might be involved. According to this hypothesis, an unknown agent interferes with the normal function of the glial genome. It stimulates the synthesis of new messenger RNA (mRNA) which specifies proteins for growth and division. The normal inverse metabolic coupling between neurone and glia is disturbed during proliferation, and as a result similar changes to those in the proliferating glia may occur in the neurone, leading to its biochemical and functional de-differentiation. The neurone may no longer be capable of synthesizing certain functional proteins, including those needed for neurotransmitter synthesis, transport and storage. As a result, though not degenerate, it would fail to act as a signalling device. Our data in support of this hypothesis are (a) that reserpine, which induces a Parkinsonism-like syndrome in man², induces increased synthesis of DNA, RNA and proteins in animals, and intense glial proliferation⁵; (b) that an increase in RNA, inversely related to melanin content, occurs in the nigral neurones of Parkinsonian patients who died during the early stages of the disease (M. I., submitted for publication); (c) that an abnormal electrophoretic pattern of blood cell proteins was found in Parkinsonian patients (H. Pataryas and C. N. S., manuscript in preparation).