Programmed axon degeneration: from mouse to mechanism to medicine

Coleman, Michael P.; Höke, Ahmet

doi:10.1038/s41583-020-0269-3

Cited by 248 publications

(250 citation statements)

References 121 publications

Supporting

Mentioning

243

Contrasting

Order By: Relevance

“…Loss of NMNAT1 in photoreceptors or NMNAT2 in axons leads to the SARM1-induced death of photoreceptors or axons, respectively. This surprising result extends our understanding of both the mechanisms causing retinal degeneration and the potential role of SARM1 in human disease ( Figley and DiAntonio, 2020 ; Coleman and Höke, 2020 ).…”

Section: Discussionsupporting

confidence: 66%

SARM1 depletion rescues NMNAT1-dependent photoreceptor cell death and retinal degeneration

Sasaki

Kakita

Kubota

et al. 2020

eLife

View full text Add to dashboard Cite

Leber congenital amaurosis type nine is an autosomal recessive retinopathy caused by mutations of the NAD+ synthesis enzyme NMNAT1. Despite the ubiquitous expression of NMNAT1, patients do not manifest pathologies other than retinal degeneration. Here we demonstrate that widespread NMNAT1 depletion in adult mice mirrors the human pathology, with selective loss of photoreceptors highlighting the exquisite vulnerability of these cells to NMNAT1 loss. Conditional deletion demonstrates that NMNAT1 is required within the photoreceptor. Mechanistically, loss of NMNAT1 activates the NADase SARM1, the central executioner of axon degeneration, to trigger photoreceptor death and vision loss. Hence, the essential function of NMNAT1 in photoreceptors is to inhibit SARM1, highlighting an unexpected shared mechanism between axonal degeneration and photoreceptor neurodegeneration. These results define a novel SARM1-dependent photoreceptor cell death pathway and identifies SARM1 as a therapeutic candidate for retinopathies.

show abstract

Section: Discussionsupporting

confidence: 66%

SARM1 depletion rescues NMNAT1-dependent photoreceptor cell death and retinal degeneration

Sasaki

Kakita

Kubota

et al. 2020

eLife

View full text Add to dashboard Cite

show abstract

“…Second, neurodegenerative diseases activate not only cell death pathways but also axonal death programs (Simon and Watkins, 2018). As synapse and axon loss is an early event in many neurodegenerative disorders (Coleman and Höke, 2020), mechanisms to maintain neuronal connectivity may need to be integrated with approaches for blocking neuronal cell death in order to maintain a functional nervous system. Finally, neurons are not the only cells affected in neurodegenerative diseases.…”

Section: Introductionmentioning

confidence: 99%

SARM1 acts downstream of neuroinflammatory and necroptotic signaling to induce axon degeneration

Milbrandt

DiAntonio

2020

Journal of Cell Biology

110

View full text Add to dashboard Cite

Neuroinflammation and necroptosis are major contributors to neurodegenerative disease, and axon dysfunction and degeneration is often an initiating event. SARM1 is the central executioner of pathological axon degeneration. Here, we demonstrate functional and mechanistic links among these three pro-degenerative processes. In a neuroinflammatory model of glaucoma, TNF-α induces SARM1-dependent axon degeneration, oligodendrocyte loss, and subsequent retinal ganglion cell death. TNF-α also triggers SARM1-dependent axon degeneration in sensory neurons via a noncanonical necroptotic signaling mechanism. MLKL is the final executioner of canonical necroptosis; however, in axonal necroptosis, MLKL does not directly trigger degeneration. Instead, MLKL induces loss of the axon survival factors NMNAT2 and STMN2 to activate SARM1 NADase activity, which leads to calcium influx and axon degeneration. Hence, these findings define a specialized form of axonal necroptosis. The demonstration that neuroinflammatory signals and necroptosis can act locally in the axon to stimulate SARM1-dependent axon degeneration identifies a therapeutically targetable mechanism by which neuroinflammation can stimulate axon loss in neurodegenerative disease.

show abstract

“…Axons in particular stand out due to their length which requires both long-range transport for delivery of cargoes to and from distant locations combined with mechanisms to ensure structural integrity (Hammarlund et al, 2007;Lorenzo et al, 2019;Maday et al, 2014). These challenges create unique vulnerabilities that are reflected in the numerous neurodevelopmental and neurodegenerative diseases that arise due to defects in axonal transport and maintenance (Coleman and Hoke, 2020;Millecamps and Julien, 2013;Sleigh et al, 2019). The unique morphology and functions of axons requires specialized organization of multiple cytoskeletal components.…”

Section: Introductionmentioning

confidence: 99%

JIP3 links lysosome transport to regulation of multiple components of the axonal cytoskeleton

Rafiq

Lyons

Gowrishankar

et al. 2020

Preprint

View full text Add to dashboard Cite

Lysosome axonal transport is important for the clearance of cargoes sequestered by the endocytic and autophagic pathways. Building on observations that mutations in the JIP3 (MAPK8IP3) gene result in lysosome-filled axonal swellings, we analyzed the impact of JIP3 depletion on the cytoskeleton of human neurons. Dynamic focal lysosome accumulations were accompanied by disruption of the axonal periodic scaffold (spectrin, F-actin and myosin II) throughout each affected axon. Additionally, axonal microtubule organization was locally disrupted at each lysosome-filled swelling.This axonal microtubule disorganization in JIP3 KO neurons was accompanied by increased tau abundance and phosphorylation. These results indicate that transport of axonal lysosomes is integrated into a much larger network that is required for the maintenance of the axonal cytoskeleton. These findings have potential relevance to human neurological disease arising from JIP3 mutations as well as for neurodegenerative tauopathies such as Alzheimer's disease.

show abstract

Programmed axon degeneration: from mouse to mechanism to medicine

Cited by 248 publications

References 121 publications

SARM1 depletion rescues NMNAT1-dependent photoreceptor cell death and retinal degeneration

SARM1 depletion rescues NMNAT1-dependent photoreceptor cell death and retinal degeneration

SARM1 acts downstream of neuroinflammatory and necroptotic signaling to induce axon degeneration

JIP3 links lysosome transport to regulation of multiple components of the axonal cytoskeleton

Contact Info

Product

Resources

About