Assays for the analysis of synaptic proteins in neurodegenerative disorders

Neurodegenerative disorders are characterized by damage to selective neuronal populations (1) that could be followed or proceeded by synaptic injury (2). The mechanisms triggering cell death and synaptic damage in these disorders might be related to gain of a toxic property and/or loss of neuroprotective capacity of a specific neuronal protein (3). Many of these neuronal molecules play an important role in the maintenance and functioning of the synaptic apparatus (4,5). Therefore, specific mutations and other alterations of synaptic proteins might result in particular neurodegenerative diseases. In this regard, recent studies have shown that molecules involved in the pathogenesis of Alzheimer's disease (AD) in fact have a synaptic location. Examples of such proteins include amyloid precursor protein (APP) (6-8), nonamyloid-β component precursor (NACP) (9), and presenilin 1 and 2 (10-12). Furthermore, other neurodegenerative disorders such as Huntington's disease (HD) (13,14), Parkinson's disease (PD) (15-17), Creutzfeldt-Jakob disease (CJD) (18), and myotonic dystrophy (19) have turned out to be the result of mutations in proteins that concentrate at the synaptic site. Therefore, in order to better understand the mechanisms of central nervous system (CNS) dysfunction in neurodegenerative disorders, it is important to determine the concentrations of specific synaptic proteins at the synaptic site, as well as to determine overall synaptic density in specific brain regions. For example, in AD, memory deficits in early stages of the disease are associated with synaptic loss in the molecular layer of the hippocampal dentate gyrus, which reflects degeneration of the perforant pathway (2,20).