PARK2 enhancement is able to compensate mitophagy alterations found in sporadic Alzheimer's disease
Patricia Martín-Maestro1, Ricardo Gargini2, George Perry3
1Centro de Biología Molecular 'Severo Ochoa' (UAM-CSIC), Nicolás Cabrera, 1. Cantoblanco, 28049 Madrid, Spain, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Valderrebollo, 5, 28031 Madrid, Spain.
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.
Insights
Mitochondrial dysfunction and impaired mitophagy are key in sporadic Alzheimer's disease (AD). Human fibroblasts reveal that fixing PARK2 can restore mitochondrial health and suggest fibroblasts are useful for studying AD.
Area of Science:
- Neuroscience
- Cell Biology
- Mitochondrial Biology
Background:
- Mitochondrial anomalies are implicated in sporadic Alzheimer's disease (AD).
- Previous studies suggest mitochondrial dysfunction in AD brain and peripheral tissues.
- The role of mitochondrial recycling in AD pathogenesis remains to be fully elucidated.
Purpose of the Study:
- To investigate mitochondrial function and recycling mechanisms in sporadic AD.
- To evaluate the role of mitophagy, lysosomes, and autophagy in AD pathogenesis.
- To validate the use of human fibroblasts as a model for sporadic AD.
Main Methods:
- Analysis of mitochondrial membrane potential recovery in patient-derived fibroblasts.
- Assessment of lysosomal and autophagic activity, including mitophagy.
- Quantification of oxidized and ubiquitinated proteins, PARK2, PINK1, and mitochondrial content.
- Comparison of fibroblast findings with human hippocampal tissue samples.
Main Results:
- Fibroblasts from sporadic AD patients showed impaired mitochondrial membrane potential recovery, altered lysosomes/autophagy, and increased protein oxidation/ubiquitination.
- Mitophagy was impaired due to reduced PARK2 and insufficient vesicle induction, leading to accumulation of depolarized mitochondria and PINK1.
- Elevated Δ1 PINK1 fragment levels inhibited PARK2 translocation, causing PINK1 accumulation.
- PARK2 overexpression reversed these deficits, restoring mitochondrial function and mitophagy.
- Sporadic AD fibroblasts mirrored early-stage hippocampal AD pathology with PINK1 and mitochondrial accumulation.
Conclusions:
- Mitophagy alterations represent a novel hallmark of sporadic Alzheimer's disease.
- PARK2 plays a critical role in regulating mitophagy and mitigating AD-related mitochondrial dysfunction.
- Human fibroblasts serve as a valid and effective model for studying sporadic AD pathology.
Related Concept Videos
01:26Alzheimer's Disease: Overview
The clinical diagnosis of AD hinges on the presence of memory and other cognitive impairments. Biomarkers, such as changes in Aβ...
01:22Alzheimer's Disease: Treatment