Research

The Hensel lab focuses on the mechanisms of Spinal Muscular Atrophy (SMA), a fatal neurodegenerative disease mainly affecting infants and children. We are not only interested in understanding the disease to help the patients, but to learn from SMA-mechanisms for other diseases. SMA is caused by low levels of a single protein, the so-called Survival of Motor Neuron (SMN) protein. SMN-deficiency leads to the degeneration of specialized neurons located in the spinal cord. These motor neurons control muscle contraction, and loss of those neurons in SMA patients results in muscle weakness and muscular atrophy. Although new therapies change the clinical landscape, still the disease is fatal for many SMA infants and children. We employ our findings in SMA-linked pathology to help characterize related neuromuscular disorders such as Amyotrophic Lateral Sclerosis (ALS), but also non-neuronal diseases like some forms of cancer.

Projects:

SMA is a hereditary disease caused by the deletion of a single gene, the so-called Survival Motor Neuron 1 (SMN1) gene leading to low levels of SMN protein. However, the molecular downstream mechanisms associated with motor neuron degeneration still are unknown. Previously, we were able to describe a molecular network of dysregulated proteins in several SMA models. Within this network, we identified B-Raf as a central hub and a potential key player in motor neuron degeneration. B-Raf is known for its neurotrophic properties promoting neuronal survival. In addition to its role in SMA, we aim to elucidate B-Raf’s neurotrophic potential in other neurodegenerative disease contexts. The project is funded by the German Research Foundation (DFG).

SMN production is not restricted to motor neurons – all cells of the body contain the SMN protein. Not surprisingly, SMA patients develop phenotypes in many different cells and organs. SMA patients and models show an impaired glucose metabolism accompanied by morphological changes of the pancreas. The pancreas itself is smaller and pancreatic islet cell-composition is altered. The molecular mechanisms underlying these changes remain unknown. What is SMN’s function in the Langerhans islets as well as the exocrine pancreas? Can too much SMN be harmful? We aim to answer these questions by employing pancreatic cell lines and pancreatic cancer models.

In May 2020 the gene-replacement therapy Zolgensma® has been approved in the EU for the treatment of SMA-patients. It is an AAV which is genetically modified to increase the SMN protein level in SMA patients. Although Zolgensma® treatment results in impressive benefits for the patients, SMA is not at all cured yet. Still there are patients who do not respond to the treatment, others poorly respond and many questions still remain. Apart from motor neurons, what is the impact of the treatment on other cells and organs? Do organs regenerate? And which organs regenerate better, which worse? Those questions are addressed within a project funded by European patient organization SMA-Europe.

Similar to SMA, ALS is characterized by loss of motor neurons within the spinal cord. Although some genes such as SOD1, TDP-43, C9ORF72, FUS and PFN1 have been identified as genetic factors causing ALS, the common mechanisms remain unknown. Besides muscular weakness and atrophy, another mutual hallmark is aggregate formation within motor neurons, but many open questions remain. How exactly do aggregates lead to motor neuron death? Does B-Raf play a role? Does B-Raf manipulation and signal modification alter disease progression? We aim to answer these questions employing a broad range of molecular and biochemical techniques.