neurodegenerative diseases, toxic protofibrillar intermediate
The highly prevalent neurodegenerative diseases Alzheimer's (AD), Parkinson's (PD), and Amyotrophic Lateral Sclerosis (ALS) have managed to elude countless efforts directed at understanding their causative agents and pathogenesis. Each of these diseases is characterized by abnormal protein aggregation under an unknown modi operandi we have determined to illuminate. AD pathology consists of neurofibrillary tangles and b-amyloid plaques in numerous brain regions, most importantly the hippocampus. Our studies have focused on b-amyloid plaques, and we have demonstrated that a protofibrillar intermediate exists in the pathway from monomeric b-amyloid to fibril and plaque formation. Our studies of the a-Synuclein aggregates characteristic of PD, known as Lewy Bodies, have revealed a protofibrillar species that may be critical in PD pathogenesis. Our studies of ALS have focused on superoxide dismutase-1 (SOD1) because previous studies have demonstrated that the A4N mutation in SOD1 leads to increased susceptibility to disease and forms aggregates within spinal motor neurons but not fibrils. We have shown that the SOD1 functions properly as a dimer and forms aggregates when it dissociates into monomers. We subsequently found a molecule that stabilized the dimer and prevented aggregation. These three neurodegenerative diseases all refer to common theme, which is abnormal protein aggregation. Our research has led us to support the hypothesis that, in the cases of PD and AD, a toxic protofibrillar intermediate is the causative agent in each disease. Treatment methods aimed at blocking protofibril formation may prove to be most effective.
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