Research Technician II
Thomas D. McCaffery, Wolf N. Hahn, Marie-Alexandre Adom, Tim E. Moors, Maria Ericcson, Dennis J. Selkoe, Ulf Dettmer, Silke Nuber
Dr. Silke Nuber
Research Category: Neurosciences
Synucleinopathies such as Parkinson’s disease (PD) and Dementia with Lewy bodies (DLB) are characterized by motor and cognitive impairments associated with progressive oligomerization and fibrillization of α-synuclein (αSyn). Amid some controversy, data from our and other labs have emerged which suggest that native αSyn forms α-helical multimers (principally tetramers) that stabilize the protein against formation of toxic αSyn aggregates. Here, we develop novel mouse models of PD/DLB using familial PD-relevant G51D-type mutations in αSyn that we have shown to abrogate the physiological tetramers. We observe accumulation of soluble αSyn monomers, their truncation and their aggregation in somata and neurites of nigra, striatum, cortex and hippocampus, accompanied by a progressive motor syndrome, including prominent slowing in gait that is responsive in part to treatment with L-DOPA. In summary, we have generated novel fPD G51D-type αSyn transgenic mice that support the importance of a physiological tetramer:monomer ratio in preventing PD. Abrogating this equilibrium leads to adverse pathological aggregates centrally implicated in the synucleinopathies.
Here, we characterize novel Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) model mice by inducing a shift in the α-synuclein (aS) conformation that modulates very early αS dyshomeostasis in neurons. PD and DLB are characterized by the progressive accumulation of misfolded αS that forms toxic aggregates in neurons. We and other laboratories showed that αS occurs in part as tetramers (4 units wound together) that resists aggregation and familial PD αS mutations decrease the normal tetramer:monomer ratio. We generated novel mouse models that express the fPD G51D mutation in addition to mice carrying an amplification (‘3D’). The overexpression of these mutants resulted in an age-progressive and partially L-DOPA responsive phenotype, including slowing in gait. We found that mice carrying an amplification of the αS E46K (1K) mutation (=”3K”) showed lesser tetramers and more rapidly developed the neuropathology in regions critical for motor behavior.