Prion protein deposition and abnormal synaptic protein expression in the cerebellum in Creutzfeldt-Jakob disease.

Prion protein (PrP(C)) is a cell membrane-anchored glycoprotein, which is replaced by a pathogenic protease-resistant, beta-sheet-containing isoform (PrP(CJD) or PrP(SC)) in human and animal prion encephalopathies, including sporadic Creutzfeldt-Jakob disease. Cell fractionation methods show that PrP(C) localizes in presynaptic membrane-enriched fractions. Following infection, abnormal PrP accumulates in nerve cell processes and synaptic regions. The present study examines the possible correlation between abnormal PrP deposition and the expression of synaptic proteins controlling neurotransmission in the cerebellum of six 129 Met/Met sporadic cases of Creutzfeldt-Jakob disease. Aggregates of protease-resistant PrP-positive granules, reminiscent of cerebellar glomeruli, were found in the granular cell layer, whereas fine punctate PrP-immunoreactive deposits occurred in the molecular layer. Small numbers of diffuse, irregular plaque-like PrP deposits in the molecular and granular cell layers were present in every case. The somas of Purkinje cells, and stellate, basket and Golgi neurons, were not immunostained. PrP-immunoreactive fibres were found in the album of the cerebellum and hilus of the dentate nucleus. Punctate PrP deposition decorated the neuropil of the dentate nucleus and the surface of dentate neurons. Synaptic protein expression was examined with synaptophysin, synapsin-1, synaptosomal-associated protein of 25,000 mol. wt, syntaxin-1 and Rab3a immunohistochemistry. Reduced synaptophysin, synapsin-1, synaptosomal-associated protein of 25,000 mol. wt, syntaxin-1 and Rab3a immunoreactivity was noted in the granular cell layer in every case, but reduced expression was inconstant in the molecular layer. Synaptophysin accumulated in axon torpedoes, thus indicating abnormal axon transport. Expression of synaptic proteins was relatively preserved in the dentate nucleus, although synaptophysin immunohistochemistry disclosed large coarse pericellular terminals in Creutzfeldt-Jakob disease, instead of the fine granular terminals in control cases, around the soma of dentate neurons. Finally, Rab3a accumulated in the cytoplasm of Purkinje cells, thus suggesting major anomalies in Rab3a transport. These observations demonstrate, for the first time, abnormal expression of crucial synaptic proteins in the cerebellum of cases with Creutzfeldt-Jakob disease. However, abnormal PrP deposition is not proportional to the degree of reduction of synaptic protein expression in the different layers of the cerebellar cortex and in the dentate nucleus. Therefore, it remains to be elucidated how abnormal PrP impacts on the metabolism of proteins linked to exocytosis and neurotransmission, and how abnormal PrP deposition results in eventual synaptic loss.