Studies

Hexanucleotide repeat expansions within C9orf72 are a frequent cause of amyotrophic lateral sclerosis and frontotemporal dementia. Haploinsufficiency leading to reduced C9orf72 protein contributes to disease pathogenesis. C9orf72 binds SMCR8 to form a robust complex that regulates small GTPases, lysosomal integrity, and autophagy. In contrast to this functional understanding, we know far less about the assembly and turnover of the C9orf72-SMCR8 complex. Loss of either subunit causes the concurrent ...

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 ...

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 ...

The metalloprotease ADAM10 is a drug target in Alzheimer's disease, where it cleaves the amyloid precursor protein (APP) and lowers amyloid-beta. Yet, ADAM10 has additional substrates, which may cause mechanism-based side effects upon therapeutic ADAM10 activation. However, they may also serve-in addition to APP-as biomarkers to monitor ADAM10 activity in patients and to develop APP-selective ADAM10 activators. Our study demonstrates that one such substrate is the neuronal cell adhesion protein ...

Microglial dysfunction is a key pathological feature of Alzheimer´s disease (AD), but little is known about proteome-wide changes in microglia during the course of AD pathogenesis and their consequences for microglial function. Here, we performed an in-depth proteomic characterization of microglia in two AD mouse models, the overexpression APPPS1 and the knock-in AppNL-G-F (APP-KI) model. Proteome changes were followed from pre-deposition to early, middle and advanced stages of amyloid plaque ...

To study mechanisms of neurodegenerative diseases, neuronal cell lines are important model systems and are often differentiated into postmitotic neuron-like cells to resemble more closely primary neurons obtained from brains. One such cell line is the Lund Human Mesencephalic (LUHMES) cell line which can be differentiated into dopamine-like neurons and is frequently used to study mechanisms of Parkinson’s disease (PD) and neurotoxicity. Neuronal differentiation of LUHMES cells is commonly verified ...

Signal peptide peptidase (SPP) and the four homologous SPP-like (SPPL) proteases constitute a family of intramembrane aspartyl proteases with selectivity for type II-oriented transmembrane segments. Here, we have analysed the physiological function of the orphan protease SPPL2c, previously considered to represent a non-expressed pseudogene. We identified proteolytic activity of SPPL2c towards selected tail-anchored proteins. Despite shared ER localization, SPPL2c and SPP exhibit distinct, though ...