Mitophagy Failure in Fibroblasts and iPSC-Derived Neurons of Alzheimer's Disease-Associated Presenilin 1 Mutation
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Published on: February 23, 2024
Patricia Martín-Maestro1,2,3, Ricardo Gargini1, Andrew A Sproul4
1Departamento de Neurobiología, Centro de Biología Molecular "Severo Ochoa" (UAM-CSIC)Madrid, Spain.
Abstract:
Familial Alzheimer's disease (FAD) is clearly related with the accumulation of amyloid-beta (Aβ) and its deleterious effect on mitochondrial function is well established. Anomalies in autophagy have also been described in these patients. In the present work, functional analyses have been performed to study mitochondrial recycling process in patient-derived fibroblasts and neurons from induced pluripotent stem cells harboring the presenilin 1 mutation A246E. Mitophagy impairment was observed due to a diminished autophagy degradation phase associated with lysosomal anomalies, thus causing the accumulation of dysfunctional mitochondria labeled by Parkin RBR E3 ubiquitin protein ligase (PARK2). The failure of mitochondrial recycling by autophagy was enhanced in the patient-derived neuronal model. Our previous studies have demonstrated similar mitophagy impairment in sporadic Alzheimer's disease (AD); therefore, our data indicate that mitophagy deficiency should be considered a common nexus between familial and sporadic cases of the disease.
Insights
Familial Alzheimer's disease (FAD) involves impaired mitophagy, a cellular recycling process. This study shows lysosomal issues cause dysfunctional mitochondria buildup in FAD, linking it to sporadic Alzheimer's disease (AD).
Area of Science:
- Neuroscience
- Cell Biology
- Genetics
Background:
- Familial Alzheimer's disease (FAD) is linked to amyloid-beta accumulation and mitochondrial dysfunction.
- Autophagy anomalies are observed in FAD patients.
Purpose of the Study:
- To investigate mitochondrial recycling via mitophagy in patient-derived cells with a presenilin 1 mutation.
- To understand the role of mitophagy in familial and sporadic Alzheimer's disease.
Main Methods:
- Functional analyses were performed on fibroblasts and induced pluripotent stem cell-derived neurons from FAD patients (presenilin 1 A246E mutation).
- Assessed mitophagy impairment, lysosomal function, and accumulation of dysfunctional mitochondria (Parkin-labeled).
Main Results:
- Mitophagy impairment was observed, characterized by a reduced autophagy degradation phase and lysosomal anomalies.
- Dysfunctional mitochondria accumulated due to impaired recycling, particularly in patient-derived neurons.
- This mitophagy deficiency was previously observed in sporadic Alzheimer's disease.
Conclusions:
- Mitophagy impairment, driven by lysosomal dysfunction, contributes to mitochondrial accumulation in familial Alzheimer's disease.
- Mitophagy deficiency represents a common pathological link between familial and sporadic Alzheimer's disease.
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