Single injection of small-molecule amyloid accelerator results in cell death of nigral dopamine neurons in mice
Artikel i vetenskaplig tidskrift, 2015

© 2015 Parkinson's Disease Foundation/Macmillan Publishers Limited.The assembly process of α-synuclein toward amyloid fibers is linked to neurodegeneration in Parkinson's disease. In the present study, we capitalized on the in vitro discovery of a small-molecule accelerator of α-synuclein amyloid formation and assessed its effects when injected in brains of normal mice. An accelerator and an inhibitor of α-synuclein amyloid formation, as well as vehicle only, were injected into the striatum of normal mice and followed by behavioral evaluation, immunohistochemistry, and metabolomics up to six months later. The effects of molecules injected into the substantia nigra of normal and α-synuclein knockout mice were also analyzed. When accelerator or inhibitor was injected into the brain of normal mice no acute compound toxicity was found. However, 6 months after single striatal injection of accelerator, mice sensorimotor functions were impaired, whereas mice injected with inhibitor had no dysfunctions. Injection of accelerator (but not inhibitor or vehicle) into the substantia nigra revealed significant loss of tyrosine hydroxylase (TH)-positive neurons after 3 months. No loss of TH-positive neurons was found in α-synuclein knock-out mice injected with accelerator into the substantia nigra. Metabolic serum profiles from accelerator-injected normal mice matched those of newly diagnosed Parkinson's disease patients, whereas the profiles from inhibitor-injected normal mice matched controls. Single inoculation of a small-molecule amyloid accelerator may be a new approach for studies of early events during dopamine neurodegeneration in mice.

Författare

M. Chermenina

Umeå universitet

E. Chorell

Umeå universitet

M. Pokrzywa

H. Antti

Umeå universitet

F. Almqvist

Umeå universitet

I. Strömberg

Umeå universitet

Pernilla Wittung Stafshede

Chalmers, Biologi och bioteknik, Kemisk biologi

Parkinsons Disease

2042-0080 (ISSN) 2090-8083 (eISSN)

Vol. 1

Ämneskategorier

Biokemi och molekylärbiologi

Biologiska vetenskaper

Biofysik

DOI

10.1038/npjparkd.2015.24

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Senast uppdaterat

2018-02-27