Natural killer cells modulate motor neuron-immune cell cross talk in models of Amyotrophic Lateral Sclerosis

AbstractIn amyotrophic lateral sclerosis (ALS), immune cells and glia contribute to motor neuron (MN) degeneration. We report the presence of NK cells in post-mortem ALS motor cortex and spinal cord tissues, and the expression of NKG2D ligands on MNs. Using a mouse model of familial-ALS, hSOD1G93A, we demonstrate NK cell accumulation in the motor cortex and spinal cord, with an early CCL2-dependent peak. NK cell depletion reduces the pace of MN degeneration, delays motor impairment and increases survival. This is confirmed in another ALS mouse model, TDP43A315T. NK cells are neurotoxic to hSOD1G93A MNs which express NKG2D ligands, while IFNγ produced by NK cells instructs microglia toward an inflammatory phenotype, and impairs FOXP3+/Treg cell infiltration in the spinal cord of hSOD1G93A mice. Together, these data suggest a role of NK cells in determining the onset and progression of MN degeneration in ALS, and in modulating Treg recruitment and microglia phenotype.

Download Full-text

Faculty Opinions recommendation of Blocking the mitochondrial apoptotic pathway preserves motor neuron viability and function in a mouse model of amyotrophic lateral sclerosis.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.5579962.6144054 ◽

2010 ◽

Author(s):

Roger Barker ◽

Wei-Li Kuan

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Mouse Model ◽

Motor Neuron ◽

Apoptotic Pathway ◽

Mitochondrial Apoptotic Pathway ◽

And Function ◽

Lateral Sclerosis

Download Full-text

A longitudinal DTI and histological study of the spinal cord reveals early pathological alterations in G93A-SOD1 mouse model of amyotrophic lateral sclerosis

Experimental Neurology ◽

10.1016/j.expneurol.2017.03.018 ◽

2017 ◽

Vol 293 ◽

pp. 43-52 ◽

Cited By ~ 12

Author(s):

Stefania Marcuzzo ◽

Silvia Bonanno ◽

Matteo Figini ◽

Alessandro Scotti ◽

Ileana Zucca ◽

...

Keyword(s):

Spinal Cord ◽

Amyotrophic Lateral Sclerosis ◽

Mouse Model ◽

Histological Study ◽

G93a Sod1 Mouse ◽

Sod1 Mouse ◽

G93a Sod1 ◽

Lateral Sclerosis

Download Full-text

In vitroactivation of GAT1 transporters expressed in spinal cord gliosomes stimulates glutamate release that is abnormally elevated in the SOD1/G93A(+) mouse model of amyotrophic lateral sclerosis

Journal of Neurochemistry ◽

10.1111/j.1471-4159.2010.06628.x ◽

2010 ◽

Vol 113 (2) ◽

pp. 489-501 ◽

Cited By ~ 32

Author(s):

Marco Milanese ◽

Simona Zappettini ◽

Emanuela Jacchetti ◽

Tiziana Bonifacino ◽

Chiara Cervetto ◽

...

Keyword(s):

Spinal Cord ◽

Amyotrophic Lateral Sclerosis ◽

Mouse Model ◽

Glutamate Release ◽

Lateral Sclerosis ◽

Sod1 G93a Mouse

Download Full-text

Non-invasive diffusion tensor imaging detects white matter degeneration in the spinal cord of a mouse model of amyotrophic lateral sclerosis

NeuroImage ◽

10.1016/j.neuroimage.2010.12.044 ◽

2011 ◽

Vol 55 (2) ◽

pp. 455-461 ◽

Cited By ~ 34

Author(s):

Clare K. Underwood ◽

Nyoman D. Kurniawan ◽

Tim J. Butler ◽

Gary J. Cowin ◽

Robyn H. Wallace

Keyword(s):

Spinal Cord ◽

Amyotrophic Lateral Sclerosis ◽

Diffusion Tensor Imaging ◽

White Matter ◽

Mouse Model ◽

Diffusion Tensor ◽

Non Invasive ◽

White Matter Degeneration ◽

Lateral Sclerosis

Download Full-text

Motor neuron translatome reveals deregulation of SYNGR4 and PLEKHB1 in mutant TDP-43 amyotrophic lateral sclerosis models

Human Molecular Genetics ◽

10.1093/hmg/ddaa140 ◽

2020 ◽

Vol 29 (16) ◽

pp. 2647-2661 ◽

Cited By ~ 1

Author(s):

Rita F Marques ◽

Jan B Engler ◽

Katrin Küchler ◽

Ross A Jones ◽

Thomas Lingner ◽

...

Keyword(s):

Spinal Cord ◽

Amyotrophic Lateral Sclerosis ◽

Motor Neuron ◽

Symptom Onset ◽

Rna Binding ◽

Affinity Purification ◽

Disease Onset ◽

Motor Symptom ◽

Pathological Feature ◽

Lateral Sclerosis

Abstract Amyotrophic lateral sclerosis (ALS) is an incurable neurological disease with progressive loss of motor neuron (MN) function in the brain and spinal cord. Mutations in TARDBP, encoding the RNA-binding protein TDP-43, are one cause of ALS, and TDP-43 mislocalization in MNs is a key pathological feature of >95% of ALS cases. While numerous studies support altered RNA regulation by TDP-43 as a major cause of disease, specific changes within MNs that trigger disease onset remain unclear. Here, we combined translating ribosome affinity purification (TRAP) with RNA sequencing to identify molecular changes in spinal MNs of TDP-43–driven ALS at motor symptom onset. By comparing the MN translatome of hTDP-43A315T mice to littermate controls and to mice expressing wild type hTDP-43, we identified hundreds of mRNAs that were selectively up- or downregulated in MNs. We validated the deregulated candidates Tex26, Syngr4, and Plekhb1 mRNAs in an independent TRAP experiment. Moreover, by quantitative immunostaining of spinal cord MNs, we found corresponding protein level changes for SYNGR4 and PLEKHB1. We also observed these changes in spinal MNs of an independent ALS mouse model caused by a different patient mutant allele of TDP-43, suggesting that they are general features of TDP-43-driven ALS. Thus, we identified SYNGR4 and PLEKHB1 to be deregulated in MNs at motor symptom onset in TDP-43-driven ALS models. This spatial and temporal pattern suggests that these proteins could be functionally important for driving the transition to the symptomatic phase of the disease.

Download Full-text