alpha-synuclein and Cataract

From kinetic data (k, T) we calculated the thermodynamic parameters for various processes (nucleation, elongation, fibrillization, etc.) of proteinaceous diseases that are related to the β-amyloid protein (Alzheimer's), to tau protein (Alzheimer's, Pick's), to α-synuclein (Parkinson's), prion, amylin (type II diabetes), and to α-crystallin (cataract). Our calculations led to ΔG

Topics: alpha-Crystallins; alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Cataract; Diabetes Mellitus, Type 2; Energy Metabolism; Humans; Islet Amyloid Polypeptide; Oxidative Stress; Oxygen; Parkinson Disease; Singlet Oxygen; tau Proteins; Thermodynamics

Topics: Aged; alpha-Synuclein; Cataract; Cataract Extraction; Crystallins; Female; Humans; Lens, Crystalline; Male; Parkinson Disease

Many diverse human diseases are associated with protein aggregation in ordered fibrillar structures called amyloid. Amyloid formation may mediate aberrant protein interactions that culminate in neurodegeneration in Alzheimer, Huntington, and Parkinson diseases and in prion encephalopathies. Studies of protein aggregation in the brain are hampered by limitations in imaging techniques and often require invasive methods that can only be performed postmortem. Here we describe transgenic mice in which aggregation-prone proteins that cause Huntington and Parkinson disease are expressed in the ocular lens. Expression of a mutant huntingtin fragment or alpha-synuclein in the lens leads to protein aggregation and cataract formation, which can be monitored in real time by noninvasive, highly sensitive optical techniques. Expression of a mutant huntingtin fragment in mice lacking the major lens chaperone, alphaB-crystallin, markedly accelerated the onset and severity of aggregation, demonstrating that the endogenous chaperone activity of alphaB-crystallin suppresses aggregation in vivo. These novel mouse models will facilitate the characterization of protein aggregation in vivo and are being used in efficient and economical screens for chemical and genetic modifiers of disease-relevant protein aggregation.

Topics: alpha-Crystallin B Chain; alpha-Synuclein; Alzheimer Disease; Animals; Cataract; Disease Models, Animal; Gene Expression; Huntingtin Protein; Huntington Disease; Lens, Crystalline; Mice; Mice, Transgenic; Mutation; Nerve Tissue Proteins; Nuclear Proteins; Parkinson Disease