Microglia-mediated recovery from ALS-relevant motor neuron degeneration in a mouse model of TDP-43 proteinopathy.
Krista J SpillerClark R RestrepoTahiyana KhanMyrna A DominiqueTerry C FangRebecca G CanterChristopher J RobertsKelly R MillerRichard M RansohoffJohn Q TrojanowskiVirginia M-Y LeePublished in: Nature neuroscience (2018)
Though motor neurons selectively degenerate in amyotrophic lateral sclerosis, other cell types are likely involved in this disease. We recently generated rNLS8 mice in which human TDP-43 (hTDP-43) pathology could be reversibly induced in neurons and expected that microglia would contribute to neurodegeneration. However, only subtle microglial changes were detected during disease in the spinal cord, despite progressive motor neuron loss; microglia still reacted to inflammatory triggers in these mice. Notably, after hTDP-43 expression was suppressed, microglia dramatically proliferated and changed their morphology and gene expression profiles. These abundant, reactive microglia selectively cleared neuronal hTDP-43. Finally, when microgliosis was blocked during the early recovery phase using PLX3397, a CSF1R and c-kit inhibitor, rNLS8 mice failed to regain full motor function, revealing an important neuroprotective role for microglia. Therefore, reactive microglia exert neuroprotective functions in this amyotrophic lateral sclerosis model, and definition of the underlying mechanism could point toward novel therapeutic strategies.
Keyphrases
- neuropathic pain
- inflammatory response
- amyotrophic lateral sclerosis
- spinal cord
- spinal cord injury
- mouse model
- endothelial cells
- lipopolysaccharide induced
- high fat diet induced
- multiple sclerosis
- cerebral ischemia
- lps induced
- stem cells
- poor prognosis
- brain injury
- blood brain barrier
- single cell
- insulin resistance
- high glucose
- gene expression
- cell therapy
- drug induced
- long non coding rna
- mesenchymal stem cells
- skeletal muscle
- wild type
- genome wide
- pluripotent stem cells
- cerebrospinal fluid
- subarachnoid hemorrhage
- bone marrow
- roux en y gastric bypass