UNIVERSITY OF COLOGNE

25 years ago, the SMN1 gene has been discovered as the spinal muscular atrophy (SMA) disease causing gene (Lefebvre et al., Cell 1995). SMA became a paradigm for a devastating neurological disorder, where the understanding of the genetic basis let to target specific therapies with antisense oligonucleotides and gene replacement therapy, approved by the FDA and EMA (the AG-Wirth was instrumental in understanding the genetic basis and splice defects in this disorder: Brunhilde Wirth Google Scholar).

SMN has an important function in splicing and snRNP biogenesis, but why it mainly causes dysfuntion of spinal motor neurons (MNs) and neuromuscular junction (NMJs) is still largely an enigma (Hosseinibarkooie et al. Exp Rev Proteomics 2017). Taking advantage of some unique SMA phenotypic discordant families with members being fully asymptomatic despite carrying the SMN1 deletion and the same SMN2 copy number as their affected family members, we identified two SMA protective modifiers: Plastin 3 (PLS3; Oprea, Science 2006) and neurocalcin delta (NCALD, Riessland et al. Am J Hum Genet. 2017). We further proved their protective effect in various SMA animal models, including worm, zebrafish and mice. Most importantly, both modifiers pointed us towards endocytosis, as the major cellular process disturbed in SMA (Hosseinibarkooie et al., Am J Hum Genet 2016; Riessland et al., Am J Hum Genet 2017). Interactome analysis of PLS3 uncovered further important proteins that act as protective modifiers in SMA animal models and are also involved in endocytosis. These are CORO1C and CHP1 (Hosseinibarkooie et al., 2016 and Janzen et al. Brain 2018).

Importantly, impaired endocytosis and membrane trafficking has been identified in various neurodegenerative disorders including Huntington’s, Parkinson’s and Alzheimer’s Diseases, ALS and others. Non-dividing cells, like neurons, and particularly the highly polarized MNs, strongly rely on recycled material and accurate transport to the appropriate place to secure a lifetime function. Moreover, neurons and especially NMJs require a large number of synaptic vesicles able to promptly release neurotransmitters upon Ca²⁺-triggered exocytosis. Thus, endocytosis has a major role in the function of MN. While we uncovered impaired endocytosis as a major cellular pathway in SMA and demonstrated the rescuing effect by both modifiers PLS3 and NCALD, and both PLS3-interacting proteins, CHP1 and CORO1C,
we are far from understanding:
1) Which type of endocytosis is mainly disturbed?
2) What are the main protein and lipid networks affected by SMN reduced levels?
3) Which molecular pathways are counteracted by the SMA modifiers. Specifically, how does PLS3, NCALD, CORO1C or CHP1 rescue endocytosis at MN/NMJ level?

Molecular, cellular and biochemical methods in neurobiology, state of the art microscopy, FACS analysis, pH-Sensitive reporter vectors for endocytosis, single cell neuronal stimulation and recording of endocytosis, candidate selection and pathways analysis of proteome, lipidome and transcriptome data, as animal model you will use mouse models already generated in the lab. 

Theoretical and experimental knowledge in cellular and molecular biology as well as biochemistry in neurobiology. Willingness to work with mouse models.

>150 Publications
(H-Factor: 59, >13,000 citations in Google Scholar)

https://scholar.google.de/citations?user=de6jjTUAAAAJ&hl=de

Torres-Benito L*, Schneider S*, ... Wirth, B. NCALD antisense oligonucleotide therapy in addition to Nusinersen further ameliorates spinal muscular atrophy in mice.
Am J Hum Genet, 2019, 105, 221-230.

Janzen E, ...Wirth B: CHP1 reduction ameliorates spinal muscular atrophy pathology by restoring calcineurin activity and endocytosis.
Brain, 2018 Aug, 141 (8): 2343-2361

Riessland M*, Kaczmarek A*, Schneider S*, ... Wirth B: Neurocalcin delta suppression protects against spinal muscular atrophy in humans and across species by restoring impaired endocytosis.
Am J Hum Genet, 2017 Feb, 100 (2): 297-315

Hosseinibarkooie SM*, Peters M*, ...Wirth B.:The Power of Human Protective Modifiers: PLS3 and CORO1C Unravel Impaired Endocytosis in Spinal Muscular Atrophy and Rescue SMA Phenotype
Am J Hum Genet, 2016 Sept; 99(3):647-665

van Dijk FS*, Zillikens.M.C*, Micha D*, Riessland M*, ..., Wirth B, Simon MEH, Pals G: X-linked PLS3 mutations cause osteoporosis and fractures.
New Engl J Med, 2013 Oct, 369:1529-1536

Oprea GE, ... Wirth B: Plastin 3 is a protective modifier of autosomal recessive spinal muscular atrophy.
Science, 2008, 320: 524-7.

Brichta L, ... Wirth B: Valproic acid increases the SMN2 protein level: a well-known drug as a potential therapy for spinal muscular atrophy.
Hum Mol Genet, 2003;12:2481-9.

Feldkötter M, ...Wirth B: Quantitative analysis of SMN1 and SMN2 based on real-time LightCycler PCR: Fast and highly reliable heterozygosity testing and prediction of severity of spinal muscular atrophy.
Am J Hum Genet, 2002, 70:358-368.

Lorson CL*, Hahnen E*, ... Wirth B: A single nucleotide in the SMN gene regulates splicing and is responsible for spinal muscular atrophy.
Proc Natl Acad Sci USA, 1999, 96 (11):6307-6311

B. Wirth & M. Riessland, US 61/859,664, Neurocalcin Delta Inhibitors and Therapeutic and Non-Therapeutic Uses Thereof, Patent filed 29.07.2014, Patent issued in US & EU in 2018,

B. Wirth, E. Janzen, N. Mendoza-Ferreira, SM Hosseinibarkooie, EP 17172826, Calcineurin B Homologous Protein 1 Inhibitors and Therapeutic and Non-Therapeutic Uses Thereof, Patent filed 24.05. 2017, PCT/EP2018/063562