S1-04-03: Synuclein: An update

Abstract

Parkinson's disease (PD) is pathologically defined by loss of neurons in selected nuclei of the brainstem, Meynert and amygdala, and by the presence of complex protein aggregates mainly composed of abnormal a–synuclein called Lewy bodies and aberrant neurites. Increased levels of a–synuclein, mutations in the a–synuclein gene and oxidative stress lead to a–synuclein aggregation. PD is considered to be within the spectrum of Lewy body diseases together with Dementia with Lewy bodies (DLB), which is characterized by PD changes and widespread Lewy bodies and neurites in the cerebral isocortex and diencephalic nuclei. Mutations in the a–synuclein gene are associated with autosomal dominant PD and DLB, whereas mutations of genes the products of which are involved in the degradation of a–synuclein and proteins linked with PD, such as parkin and ubiquitin C–terminal hydrolase –1 (UCHL–1), are associated with sporadic, autosomal dominant or autosomal recessive Lewy body diseases. Cases with early PD changes restricted to the medulla oblongata, pons and olfactory bulb are considered pre–clinical PD. Recent studies have shown that lipoxidative and glycoxidative stress damage precedes a–synuclein aggregation in the frontal cortex in pre–clinical PD. Target proteins are synucleins and proteins related with mitochondria and redox homeostasis. Oxidative stress damage varies with disease progression in the frontal cortex in DLB. a–synuclein in Lewy body diseases is nitrated, phosphorylated and has an abnormal configuration. These modifications are associated with abnormal protein–protein interactions, mainly with rab proteins and phospholipases, which result in reduced transport of synaptic vesicles to pre–synaptic sites, and conduct to impaired activity of type I metabotropic glutamate receptors, respectively. Aggregates of a–synuclein and associated proteins are considered the result of impaired function of the ubiquitin–proteasome–system (UPS). Our observations in transgenic mice and modified cell lines have shown no modifications in the expression levels of the proteasome and in enzymatic proteasomal activities. However, UCHL–1 mRNA and protein levels are reduced in parallel with a–synuclein aggregates in Lewy body diseases, thus implicating down–regulation of UCHL–1 in the pathogenesis of sporadic PD and DLB.