Brunhilde Wirth - C 16

Unraveling the molecular and cellular mechanism underlying spinal muscular atrophy by use of genetic modifiers


Neurodegenerative diseases are widespread and have no cure. In many cases, the disease-causing genes are known, but the mechanisms underlying disease onset, progression, and pathology remains elusive. The motor neuron (MN) disease Spinal Muscular Atrophy (SMA) is caused by reduced levels of the survival of motor neuron (SMN) protein, whose function is critical for assembly of the spliceosome and other protein complexes. Despite the housekeeping function, SMN deficit in SMA patients primarily impacts the function of alpha MN, resulting in dysfunction, degeneration and consequent muscular atrophy.

We identified two human protective SMA modifiers - PLS3 and NCALD - and proved their ability to counteract SMA in vitro and in vivo using SMA zebrafish and mouse models. Both proteins and their interactome helped us to uncover endocytosis as a major cellular pathway disturbed in SMA and rescued by these modifiers. Moreover, we identified 75 novel PLS3 interacting proteins, many of which are involved in MN and neurodegenerative disorders, strengthening the broad role of PLS3 in neuronal function.

Here we aim to understand 1) which are the regulatory mechanism leading to upregulation of PLS3 and suppression of NCALD by using OMICS approaches and CRIPR-Cas9 for modelling the respective genetic variants in cellular and if applicable animal models, and 2) which type of endocytosis and signalling pathway is mainly affected by SMA and restored by the modifiers performing in vitro and in vivo analysis in mice.

Clinical/medical relevance and sustainability in disease understanding

Both aims are embedded in a large project of our lab seeking for genetic, cellular and pathological causes of neurogenetic disorders. This will facilitate the development of targeted therapies for these disorders.

We are working on SMA therapy development since many years and hold a patent on NCALD. Recently, we identified the genetic cause of five novel MN disorders, some of them are strongly related to the SMN pathway. Taken together, they will unravel the MN function in health and disease.

Selected publications

*equally contributed first authors

  1. Heesen L*, Peitz M*...Brüstle O, Wirth B. Plastin 3 is upregulated in iPSC-derived motoneurons from asymptomatic SMN1-deleted individuals. Cell Mol Life Sci. 2016; 73:2089-104.
  2. Hosseinibarkooie S*, 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; 99:647-65.
  3. Wirth B., et al . Moving towards treatments for spinal muscular atrophy: hopes and limits. Expert Opin Emerg Drugs. 2015; 20:353-6.
  4. 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, 2013,369:1529-3
  5. Ackermann B, ... Wirth B. Plastin 3 ameliorates spinal muscular atrophy via delayed axon pruning and improves neuromuscular junction functionality. Hum Mol Genet, 2013, 22:328-47
  6. Oprea GE… Wirth B. Plastin 3 is a protective modifier of autosomal recessive spinal muscular atrophy Science, 2008, 320:524-527.

Prof. Dr. Brunhilde Wirth

Institute for Human Genetics

Prof. Dr. Brunhilde Wirth

Principal Investigator C 16
Executive Board Member

Work +49 221 478 86464

Fax (Work) +49 221 478 86465

Institute for Human Genetics
Kerpener Str. 34
50931 Cologne

Publications - Brunhilde Wirth

Link to PubMed

Group Members

Seyyedmohsen Hosseinibarkooie (Postdoc)
Markus Riessland (PostDoc, currently at Rockefeller Univ.)
Markus Storbeck (PostDoc)
Laura Torres-Benito (PostDoc)
Ludwig Heesen (PhD student, completed)
Christian Hoffmann (MD student)
Eva Janzen (PhD student)
Anna Kaczmarek (PhD student, completed)
Mert Karakaya (MD student)
Lilian Martinez (PhD student)
Natalia Mendoza-Ferreira (PhD student)
Janine Milbradt (PhD student)
Miriam Peters (PhD student)
Svenja Schneider (PhD student)
Eike Strathmann (PhD student)
Aaradhita Upadhyay (PhD student)
Andrea delle Vedove (MD/PhD student)
Vanessa Grysko (technician)
Irmgard Hölker (technician)
Kristina Hupperich (technician)