Optineurin-facilitated axonal mitochondria delivery promotes neuroprotection and axon regeneration
Status PubMed-not-MEDLINE Language English Country United States Media electronic
Document type Preprint, Journal Article
Grant support
R01 EY034353
NEI NIH HHS - United States
P30 EY026877
NEI NIH HHS - United States
R01 EY024932
NEI NIH HHS - United States
S10 OD025091
NIH HHS - United States
R01 EY032518
NEI NIH HHS - United States
R01 EY023295
NEI NIH HHS - United States
F32 EY029567
NEI NIH HHS - United States
R01 EY032159
NEI NIH HHS - United States
R01 EY025295
NEI NIH HHS - United States
S10 OD030452
NIH HHS - United States
PubMed
38617277
PubMed Central
PMC11014509
DOI
10.1101/2024.04.02.587832
PII: 2024.04.02.587832
Knihovny.cz E-resources
- Publication type
- Journal Article MeSH
- Preprint MeSH
Optineurin (OPTN) mutations are linked to amyotrophic lateral sclerosis (ALS) and normal tension glaucoma (NTG), but a relevant animal model is lacking, and the molecular mechanisms underlying neurodegeneration are unknown. We found that OPTN C-terminus truncation (OPTN∆C) causes late-onset neurodegeneration of retinal ganglion cells (RGCs), optic nerve (ON), and spinal cord motor neurons, preceded by a striking decrease of axonal mitochondria. Surprisingly, we discover that OPTN directly interacts with both microtubules and the mitochondrial transport complex TRAK1/KIF5B, stabilizing them for proper anterograde axonal mitochondrial transport, in a C-terminus dependent manner. Encouragingly, overexpressing OPTN/TRAK1/KIF5B reverses not only OPTN truncation-induced, but also ocular hypertension-induced neurodegeneration, and promotes striking ON regeneration. Therefore, in addition to generating new animal models for NTG and ALS, our results establish OPTN as a novel facilitator of the microtubule-dependent mitochondrial transport necessary for adequate axonal mitochondria delivery, and its loss as the likely molecular mechanism of neurodegeneration.
Department of Cell Biology and Human Anatomy University of California Davis Davis CA; USA
Department of Electrical Engineering Stanford University Stanford CA 94305 USA
Department of Ophthalmology University of California San Francisco San Francisco CA; USA
Institute of Biotechnology Czech Academy of Sciences BIOCEV Vestec Prague West Czechia
Viterbi Family Department of Ophthalmology University of California San Diego San Diego CA; USA
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