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  • PARK2 enhancement is able to compensate mitophagy alterations found in sporadic Alzheimer's disease.

PARK2 enhancement is able to compensate mitophagy alterations found in sporadic Alzheimer's disease.

Human molecular genetics (2016-01-02)
Patricia Martín-Maestro, Ricardo Gargini, George Perry, Jesús Avila, Vega García-Escudero
ABSTRACT

Mitochondrial anomalies have been previously reported in patients' brain and peripheral tissue, suggesting their relevance in sporadic Alzheimer's disease (AD). The present work evaluates mitochondrial function and recycling in human fibroblasts and brain biopsies. Functional studies using patients' skin fibroblasts showed slower mitochondrial membrane potential recovery after a mitochondrial insult together with alterations in lysosomes and autophagy, accompanied by an increase of oxidized and ubiquitinated proteins. Impairment in mitophagy has been proven in these cells due to diminished PARK2 and insufficient vesicle induction, accumulating depolarized mitochondria and PINK1. Augmented Δ1 PINK1 fragment levels suggest an inhibitory effect over PARK2 translocation to the mitochondria, causing the accumulation of activated PINK1. Moreover, the overexpression of PARK2 diminished ubiquitinated proteins accumulation, improves its targeting to mitochondria and potentiates autophagic vesicle synthesis. This allows the reversion of mitophagy failure reflected in the recovery of membrane potential and the decrease of PINK1 and mitochondria accumulation. Sporadic AD fibroblasts exhibited alterations similar to what it could be found in patients' hippocampal samples at early stages of the disease, where there was an accumulation of PINK1 and Δ1 PINK1 together with abnormally increased mitochondrial content. Our findings indicate that mitophagy alterations can be considered a new hallmark of sporadic AD and validate the use of fibroblasts for modelling this pathology.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
OxyBlot Protein Oxidation Detection Kit, The OxyBlot Protein Oxidation Detection Kit provides the reagents to perform the immunoblot detection of carbonyl groups introduced into proteins by oxidative reactions with ozone or oxides of nitrogen or by metal catalyzed oxidation.
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Carbonyl cyanide 3-chlorophenylhydrazone, ≥97% (TLC), powder
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Oligomycin from Streptomyces diastatochromogenes, ≥90% total oligomycins basis (HPLC)
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Polyethylenimine, branched, average Mw ~25,000 by LS, average Mn ~10,000 by GPC, branched
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