Objective: To determine the role of the different mitophagy pathways involved in PD, a key question that is still unresolved. We will investigate whether a-synuclein (α-SYN) WT and with the A53T mutation can modulate (induce/repress) mitophagy in neurons and astrocytes in vivo and in vitro.
Background: Mitochondria are organelles that perform essential functions in cells regulating metabolism, reactive oxygen species generation, and most importantly the production of most of its energy. Mitophagy is a quality control pathway whereby mitochondria are specifically targeted by autophagosomes for degradation within lysosomes. Mitochondrial dysfunction is a well-established pathological hallmark of Parkinson’s disease (PD), probably due the high dependence on mitochondrial metabolism of neurons. However, whether mitophagy is altered in this disease is still a matter of intense debate.
Method: We will assess mitophagy in vivo in MitoQC reporter mice after stereological injections of WT and mutated A53T α-SYN adeno-associated expression vectors. Along with mitophagy assessment, other mitochondrial parameters will also be evaluated to characterize mitostasis. Similar in vitro analysis will be performed in N2a cells that constitutively express α-SYN or immortalized astrocyte cell line (IMA2.1) treated with recombinant α-SYN.
Results: Results showed that in vivo α-SYN-WT or α-SYN-A53T neuronal overexpression leads to a decreased mitophagy in dopaminergic neurons of SNpc, whereas increased mitophagy occurs in reactive astrocytes surrounding area. In vitro, N2a expressing α-SYN showed increased mRNA expression of PINK1/PARKIN while reducing the expression of BNIP3/NIX, indicating the involvement of different mitophagy pathways.
Conclusion: Our results indicate that α-SYN (WT or A53T) overexpression induces differentiated mitophagy mechanisms between neurons and astrocytes, key for the development of PD.
To cite this abstract in AMA style:
I. Lastres-Becker, S. Castro-Sánchez, I. Silva-Llanes, P. Teresak, JL. Lanciego, E. Sierra, P. Boya. The overexpression of a-SYN leads to a differential process of mitophagy in neurons and atrocytes [abstract]. Mov Disord. 2022; 37 (suppl 2). https://www.mdsabstracts.org/abstract/the-overexpression-of-a-syn-leads-to-a-differential-process-of-mitophagy-in-neurons-and-atrocytes/. Accessed May 16, 2025.« Back to 2022 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/the-overexpression-of-a-syn-leads-to-a-differential-process-of-mitophagy-in-neurons-and-atrocytes/