The loss of inhibitory C-terminal conformations in disease associated P123H ß-synuclein.

ß-synuclein (ßS) is a homologue of α-synuclein (αS), the major protein component of Lewy bodies in patients with Parkinson's disease. In contrast to αS, ßS does not form fibrils, mitigates αS toxicity in vivo and inhibits αS fibril formation in vitro. Previously a missense mutation of ßS, P123H, was identified in patients with Dementia with Lewy Body disease. The single P123H mutation at the C-terminus of ßS is able to convert ßS from a nontoxic to a toxic protein that is also able to accelerate formation of inclusions when it is in the presence of αS in vivo. To elucidate the molecular mechanisms of these processes, we compare the conformational properties of the monomer forms of αS, ßS and P123H-ßS, and the effects on fibril formation of coincubation of αS with ßS, and with P123H-ßS. NMR residual dipolar couplings and secondary structure propensities show that the P123H mutation of ßS renders it more flexible C-terminal to the mutation site and more αS-like. In vitro Thioflavin T fluorescence experiments show that P123H-ßS accelerates αS fibril formation upon coincubation, as opposed to wild type ßS that acts as an inhibitor of αS aggregation. When P123H-ßS becomes more αS-like it is unable to perform the protective function of ßS, which suggests that the extended polyproline II motif of ßS in the C-terminus is critical to its nontoxic nature and to inhibition of αS upon coincubation. These studies may provide a basis for understanding which regions to target for therapeutic intervention in Parkinson's disease.

Ibuprofen ameliorates protein aggregation and astrocytic gliosis, but not cognitive dysfunction, in a transgenic mouse expressing dementia with Lewy bodies-linked P123H ß-synuclein.

Epidemiological studies have shown that ibuprofen, a non-steroidal anti-inflammatory drug, reduces the risk for neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). In this context, it has been shown that chronic treatment with ibuprofen improves cognitive dysfunction and histopathologic outcome in mouse models of AD. However, the therapeutic effects of ibuprofen in animal models of PD and related synucleinopathies such as dementia with Lewy bodies (DLB) have not been investigated. Therefore, the main objective of this study was to determine if ibuprofen ameliorates neuropathology and cognitive dysfunction in a transgenic (tg) mouse expressing DLB-linked P123H ß-synuclein. P123H ß-synuclein tg mice and their non-tg littermates aged 3 months were given ibuprofen in their diet (n=13). Controls did not receive ibuprofen (n=11). After 3 months, the mice were evaluated using a Morris water maze test, followed by neuropathological analyses. Compared to control P123H ß-synuclein tg mice, P123H ß-synuclein tg mice that received ibuprofen had significantly reduced protein aggregation and astrogliosis. However, ibuprofen treatment produced little improvement of the learning disability of P123H ß-synuclein tg mice in the Morris water maze test. These results suggest that amelioration of neuropathologies by ibuprofen does not necessarily lead to improved cognitive function in synucleinopathies such as DLB.