Studies

Hereditary sensory and autonomic neuropathy 9 (HSAN9) is a rare neurological disease caused by mutations in the gene encoding for Tectonin β-propeller repeat containing protein 2 (TECPR2) which possibly result in loss of the protein. Beside its potential role in autophagy, TECPR2 may serve as positive modulator of COPII-mediated ER export. However, the molecular consequences of TECPR2 deficiency for the secretory pathway remain unclear, in particular with regard to specific cargo proteins. By ...

In the context of studying the role of the COP9 signalosome (CSN) in neuroinflammation and ischemic neuronal damage, we studied the effect of the cullin NEDDylation state-modifying drugs MLN4924 and CSN5i-3 in BV2 microglial cells, an immortalized murine cell line featuring many of the characteristics of primary microglia. Owing to its potent inhibitory effect on the NEDDylation cascade, MLN4924 exhibits a CSN5-like anti-inflammatory activity. Csn5i-3 is a small molecule inhibitor that specifically ...

While deleterious mutations are responsible for the vast majority of TBK1-linked ALS/FTD cases, the ALS/FTD causing missense mutation p.E696K leads to a selective loss of TBK1/optineurin binding. Knock-in of this specific missense mutation causes progressive autophagolysosomal dysfunction and an ALS/FTD-like phenotype in mice, while, as opposed to TBK1 deletion, RIPK/TNF-α-dependent necroptosis or overt inflammation are absent. Our results highlight the role of autophagolysosomal dysfunction as ...