Open AccessDevelopment of GMP ‐1 a molecular chaperone network modulator protecting mitochondrial function and its assessment in fly and mice models of Alzheimer's disease
Author(s) -
Pavlov Pavel F.,
HutterPaier Birgit,
Havas Daniel,
Windisch Manfred,
Winblad Bengt
Publication year - 2018
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.13624
Subject(s) - mitochondrion , chaperone (clinical) , neuroprotection , microbiology and biotechnology , hsp90 , heat shock protein , amyloid precursor protein , biology , neurodegeneration , hsp70 , dnaja3 , organelle , alzheimer's disease , mitochondrial fusion , biochemistry , neuroscience , medicine , disease , mitochondrial dna , gene , pathology
Mitochondrial dysfunction is an early feature of Alzheimer's disease ( AD ) and may play an important role in the pathogenesis of disease. It has been shown that amyloid beta peptide (Aβ) and amyloid precursor protein ( APP ) interact with mitochondria contributing to the mitochondrial dysfunction in AD . Prevention of abnormal protein targeting to mitochondria can protect normal mitochondrial function, increase neuronal survival and at the end, ameliorate symptoms of AD and other neurodegenerative disorders. First steps of mitochondrial protein import are coordinated by molecular chaperones Hsp70 and Hsp90 that bind to the newly synthesized mitochondria‐destined proteins and deliver them to the protein import receptors on the surface of organelle. Here, we have described the development of a novel compound named GMP ‐1 that disrupts interactions between Hsp70/Hsp90 molecular chaperones and protein import receptor Tom70. GMP ‐1 treatment of SH ‐ SY 5Y cells results in decrease in mitochondria‐associated APP and protects SH ‐ SY 5Y cells from toxic effect of Aβ 1‐42 exposure. Experiments in drosophila and mice models of AD demonstrated neuroprotective effect of GMP ‐1 treatment, improvement in memory and behaviour tests as well as restoration of mitochondrial function.