The Brenner lab belongs to the department of Neurology of the University of Ulm. We have a strong scientific focus on the genetics of motor neuron and other neurodegenerative diseases. We aim to identify the disease relevant mechanisms of genetic ALS subtypes employing analysis of transgenic in vitro and in vivo model systems as well as patient tissue. Currenly, we are concentraing on the ALS genes NEK1 and TBK1. The ultimate goal of our research is to impact genetic counselling of variants of uncertain significance and fuel the identification of specific biomarkers and pharmacological targets for future clinical trials.
NEK1 and ALS
Mutations in the NEK1 gene (NEK1-ALS) are the third and fifth most frequent genetic cause of sporadic and familial ALS, respectively. Since its discovery as an ALS gene (Brenner et al., 2016; Higelin et al., 2018), the pathomechanistic workup of the NEK1 gene in the ALS context has been virtually absent – despite its proportional importance. We recently teamed-up with Dr. Catanese’s lab at the inistitute of anatomy to identify the molecular mechanisms underlying ALS linked to mutations in the NEK1 gene (NEK1-ALS). To that end we use multi-omic and hypothesis-driven differential analyses of isogenic and patient-derived iPSC-derived motor neurons bearing NEK1 loss-of-function and missense variants followed by validation in NEK1-mutant mouse models and CNS autopsy tissue from NEK1-ALS patients (cooperation with University of Umea).
TBK1 and ALD/FTD
Heterozygous loss-of function variants in the TBK1 gene are a cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). TBK1 is a pleiotropic kinase that is an important inductor of selective autophagy and type I IFN signaling. We and others have previously shown that deletion of Tbk1 impairs selective autophagy in spinal motor neurons and prepones the onset of motor symptoms in the SOD1G93A mouse model for ALS but at the later disease stage alleviates neurotoxic glial neuroinflammation and thus slows down disease progression. These findings indicate that TBK1 in motor neurons is protective at the early stage but harmful at the late stage of ALS in mice. The finding that a motor neuron selective knock-out (KO) of Tbk1 is sufficient to alleviate the neurotoxic glial inflammation in these mice strongly suggests that TBK1 in motor neurons mediates a fatal neuroglial crosstalk that recruits glial cells to the anterior horns which fuel neurodegeneration. In cooperation with other groups we are investigating through which pathway TBK1 in motor neurons mediates this neuroglial crosstalk using transgenic in vitro and in vivo model systems.
Lafora progressive myoclonus epilepsy (Lafora disease) is a rare, usually childhood-onset, fatal neurodegenerative disease caused by biallelic mutations in EPM2A (Laforin) or EPM2B (NHLRC1, Malin). Pathogenic homozygous or compound heterozygous mutations in both genes cause cytoplasmatic precipitation, aggregation and accumulation of neurotoxic poorly branched and insoluble glycogen forming polyglucosan inclusions (so-called Lafora bodies) leading to progressive neurodegeneration. In most cases, the disease starts with epileptic seizures in late childhood or adolescence. Apart from multiple types of seizures (tonic-clonic, myoclonic, absence, atonic, or visual), LD patients develop progressive cerebellar ataxia, dysarthria, dementia and neuropsychiatric symptoms. LD usually leads to death within 10 years after symptom onset. At present, therapy is merely symptomatic and palliative. Recent preclinic studies have shown that downregulation of glycogen synthesis prevents LD in mice. Our research on Lafora disease (in cooperation with other labs of the Ulm Neurology dpt.) focuses on the identification of diagnostic and therapeutic biomarkers of the disease.