期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 116, 期 2, 页码 650-659出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1811021116
关键词
neurodegeneration; mitochondrial membrane potential; neurite retraction; caspase-3; mutant huntingtin
资金
- National Institute of Neurological Disorders and Stroke Grants [R01NS089688, R01NS039324, R01NS077748, R01NS100743]
- David Scaife Family Charitable Foundation
- University of Pittsburgh Brain Institute
- Walter L. Copeland Fund of the Pittsburgh Foundation
Neuritic retraction in the absence of overt neuronal death is a shared feature of normal aging and neurodegenerative disorders, but the intracellular mechanisms modulating this process are not understood. We propose that cumulative distal mitochondrial protein damage results in impaired protein import, leading to mitochondrial dysfunction and focal activation of the canonical apoptosis pathway in neurites. This is a controlled process that may not lead to neuronal death and, thus, we term this phenomenon neuritosis. Consistent with our hypothesis, we show that in primary cerebrocortical neurons, mitochondrial distance from the soma correlates with increased mitochondrial protein damage, PINK1 accumulation, reactive oxygen species production, and decreased mitochondrial membrane potential and depolarization threshold. Furthermore, we demonstrate that the distance-dependent mitochondrial membrane potential gradient exists in vivo in mice. We demonstrate that impaired distal mitochondria have a lower threshold for focal/nonlethal neuritic caspase-3 activation in normal neurons that is exacerbated in aging, stress, and neurodegenerative conditions, thus delineating a fundamental mechanistic underpinning for synaptic vulnerability.
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