REDUCED EXPRESSION OF PREPROENKEPHALIN IN STRIATAL NEURONS FROM HUNTINGTONS-DISEASE PATIENTS

Differential loss of neurons and terminals occurs in Huntington's dise ase. Neurons expressing preproenkephalin (PPE) appear to be more vulne rable than neurons expressing preprotachykinin and terminals in the la teral pallidum (containing enkephalin) are more affected than terminal s in the medial pallidum (containing substance P). We used in situ hyb ridization histochemistry and emulsion autoradiography to quantify the number of PPE expressing neurons and the neuronal levels of PPE mRNA in striatum of individuals who died with Huntington's disease and norm al controls. We found a grade-related decline in the number of PPE-lab eled neurons per field in the striatum of individuals with Huntington' s disease compared with controls. Three measures of the neuronal level of PPE mRNA, the mean number of silver grains per PPE neuron, the med ian number of grains per PPE neuron, and the percentage of PPE neurons with more than 30 grains, were all significantly reduced (41 to 80% o f control) in Huntington's disease striatum. The magnitude of the redu ction in levels of PPE mRNA per neuron was related to the grade of les ions. These data support the notion that decreased levels of PPE mRNA may account, in part, for the greater loss of enkephalin staining in l ateral pallidal terminals compared with substance P staining in medial pallidal terminals. Decreased levels of PPE mRNA may result in clinic al symptoms prior to the loss of neurons. The reduction in expression of PPE mRNA suggests that surviving striatal neurons may be affected b y the expression of the Huntington's disease gene prior to their immin ent cell death.