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

Prion protein (PrPC) is a cell membrane-anchored glycoprotein, which is rep laced by a pathogenic protease-resistant, beta-sheet-containing isoform (Pr PCJD or PrPSC) in human and animal prion encephalopathies, including sporad ic Creutzfeldt-Jakob disease. Cell fractionation methods show that PrPC loc alizes in presynaptic membrane-enriched fractions. Following infection, abn ormal PrP accumulates in nerve cell processes and synaptic regions. The pre sent study examines the possible correlation between abnormal PrP depositio n and the expression of synaptic proteins controlling neurotransmission in the cerebellum of six 129 Met/Met sporadic cases of Creutzfeldt-Jakob disea se. Aggregates of protease-resistant PrP-positive granules, reminiscent of cerebellar glomeruli, were found in the granular cell layer, whereas fine p unctate 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 cel ls, and stellate, basket and Golgi neurons, were not immunostained. PrP-imm unoreactive fibres were found in the album of the cerebellum and hilus of t he dentate nucleus. Punctate PrP deposition decorated the neuropil of the d entate nucleus and the surface of dentate neurons. Synaptic protein express ion was examined with synaptophysin, synapsin-l, synaptosomal-associated pr otein of 25,000 mel. wt, syntaxin-1 and Rab3a immunohistochemistry. Reduced synaptophysin, synapsin-l, synaptosomal-associated protein of 25,000 mel, wt, syntaxin-1 and Rab3a immunoreactivity was noted in the granular cell la yer in every case, but reduced expression was inconstant in the molecular l ayer. Synaptophysin accumulated in axon torpedoes, thus indicating abnormal axon transport. Expression of synaptic proteins was relatively preserved i n the dentate nucleus, although synaptophysin immunohistochemistry disclose d large coarse pericellular terminals in Creutzfeldt-Jakob disease, instead of the fine granular terminals in control cases, around the soma of dentat e neurons. Finally, Rab3a accumulated in the cytoplasm of Purkinje cells, t hus 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 degre e of reduction of synaptic protein expression in the different layers of th e cerebellar cortex and in the dentate nucleus. Therefore, it remains to be elucidated how abnormal PrP impacts on the metabolism of proteins Linked t o exocytosis and neurotransmission, and how abnormal PrP deposition results in eventual synaptic loss. (C) 2000 ZERO. Published by Elsevier Science Lt d.