|
|
|
|
LEADER |
02807nam a2200409Ia 4500 |
001 |
10-1007-s00401-022-02406-7 |
008 |
220420s2022 CNT 000 0 und d |
020 |
|
|
|a 00016322 (ISSN)
|
245 |
1 |
0 |
|a Brain region-specific susceptibility of Lewy body pathology in synucleinopathies is governed by α-synuclein conformations
|
260 |
|
0 |
|b Springer Science and Business Media Deutschland GmbH
|c 2022
|
300 |
|
|
|a 17
|
856 |
|
|
|z View Fulltext in Publisher
|u https://doi.org/10.1007/s00401-022-02406-7
|
520 |
3 |
|
|a The protein α-synuclein, a key player in Parkinson’s disease (PD) and other synucleinopathies, exists in different physiological conformations: cytosolic unfolded aggregation-prone monomers and helical aggregation-resistant multimers. It has been shown that familial PD-associated missense mutations within the α-synuclein gene destabilize the conformer equilibrium of physiologic α-synuclein in favor of unfolded monomers. Here, we characterized the relative levels of unfolded and helical forms of cytosolic α-synuclein in post-mortem human brain tissue and showed that the equilibrium of α-synuclein conformations is destabilized in sporadic PD and DLB patients. This disturbed equilibrium is decreased in a brain region-specific manner in patient samples pointing toward a possible “prion-like” propagation of the underlying pathology and forms distinct disease-specific patterns in the two different synucleinopathies. We are also able to show that a destabilization of multimers mechanistically leads to increased levels of insoluble, pathological α-synuclein, while pharmacological stabilization of multimers leads to a “prion-like” aggregation resistance. Together, our findings suggest that these disease-specific patterns of α-synuclein multimer destabilization in sporadic PD and DLB are caused by both regional neuronal vulnerability and “prion-like” aggregation transmission enabled by the destabilization of local endogenous α-synuclein protein. © 2022, The Author(s).
|
650 |
0 |
4 |
|a Aggregation
|
650 |
0 |
4 |
|a Aggregation transmission
|
650 |
0 |
4 |
|a DLB
|
650 |
0 |
4 |
|a Multimers
|
650 |
0 |
4 |
|a PD
|
650 |
0 |
4 |
|a α-Synuclein
|
700 |
1 |
0 |
|a Bartels, T.
|e author
|
700 |
1 |
0 |
|a Cantlon, A.
|e author
|
700 |
1 |
0 |
|a de Boni, L.
|e author
|
700 |
1 |
0 |
|a Dettmer, U.
|e author
|
700 |
1 |
0 |
|a Jaunmuktane, Z.
|e author
|
700 |
1 |
0 |
|a Jiang, H.
|e author
|
700 |
1 |
0 |
|a Kim, N.
|e author
|
700 |
1 |
0 |
|a Lashley, T.
|e author
|
700 |
1 |
0 |
|a Liu, L.
|e author
|
700 |
1 |
0 |
|a Martin, E.
|e author
|
700 |
1 |
0 |
|a Rovere, M.
|e author
|
700 |
1 |
0 |
|a Sanderson, J.
|e author
|
700 |
1 |
0 |
|a Sylvester, M.
|e author
|
700 |
1 |
0 |
|a Wallis, A.
|e author
|
700 |
1 |
0 |
|a Watson, A.H.
|e author
|
700 |
1 |
0 |
|a Zaccagnini, L.
|e author
|
700 |
1 |
0 |
|a Zhelcheska, K.
|e author
|
773 |
|
|
|t Acta Neuropathologica
|