Dynamics of Autophagy and Mitophagy in Neurons

Identification: Holzbaur, Erika


Dynamics of Autophagy and Mitophagy in Neurons
Erika Holzbaur1
1University of Pennsylvania Perelman School of Medicine
Neurons are post-mitotic and highly polarized cells with processes that can extend up to 1 m, making them highly vulnerable to defects in proteostasis and organelle turnover.  We are characterizing two major autophagy pathways in primary neurons, a constitutive pathway for axonal autophagy and a damage-induced pathway that is selective and occurs primarily in the soma.  In the axon, autophagosomes are formed constitutively at the axon terminal, and then are rapidly translocated toward the soma by cytoplasmic dynein.  Maturation, involving lysosomal fusion and acidification to a degradation-competent compartment, occurs en route.  This pathway for constitutive axonal autophagy is robust in neurons from young mice, but becomes specifically disrupted with aging, leading to the formation of stalled autophagic vacuoles in the distal axon.  This aging-induced dysfunction in axonal autophagy may contribute to the age-associated onset of pathogenesis in neurodegenerative disease.  We are also investigating the selective removal of damaged mitochondria, which occurs via a distinct pathway involving the mitophagy receptor optineurin and the kinase TBK1, operating downstream of PINK1 and Parkin.  In primary hippocampal neurons, the pathway for selective removal of mitochondria by mitophagy is both biochemically and spatially distinct from the constitutive pathway for non-selective autophagy in the axon.  As mutations in optineurin, TBK1, PINK1 and Parkin induce neurodegenerative disease, we propose that both the axonal pathway and the damaged-induced pathway are required to maintain neuronal homeostasis.


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