VIB-KU Leuven Center for Brain & Disease Research Virtual visit to our lab Lab of Neurobiology

Disease focus

ALS & FTD

We study ALS and FTD. ALS is a neurodegenerative disorder characterized by a rather selective motor neuron death, resulting in progressive paralysis and death of patients 2 to 5 years after disease onset (Cleveland and Rothstein, 2001). FTD is a dementia syndrome characterized by early changes in language, personality or behavior with marked degeneration in the prefrontal and anterior temporal cortex (Neary et al., 2005). No effective treatments exist. Both neurodegenerative disorders are familial in some patients (~10% of ALS and 20-40% of FTLD cases, mostly dominantly inherited), but in the majority of cases, there is no familial history (so-called ‘sporadic cases’).

The most common genetic causes of ALS are mutations in

  • C9orf72 (DeJesus-Hernandez et al., 2011; Renton et al., 2011),
  • superoxide dismutase 1 (SOD1) (Rosen et al., 1993), and
  • the genes of the DNA/RNA binding proteins TDP-43 (TARDBP) (Kabashi et al., 2008; Sreedharan et al., 2008) and FUS (Kwiatkowski et al., 2009; Vance et al., 2009).
     

For TFD, the most common gene mutations are in

  • tau (MAPT) (Hutton et al., 1998),
  • progranulin (GRN) (Baker et al., 2006; Cruts et al., 2006) and
  • C9orf72 (DeJesus-Hernandez et al., 2011; Renton et al., 2011).

In the last few years, several additional ALS-FTD genes have been discovered. Although most of them are not frequently encountered in patients, they hint at important disease pathways. At the neuropathological level, protein aggregates containing TDP-43, ubiquitin, and p62 are observed in the majority of ALS patients and in about 50% of FTD patients.

We aim to identify modifiers of the disease and to better understand the mechanisms of neurodegeneration in ALS and FTD using a variety of disease models. For different forms of hereditary ALS or FTD, we have previously generated small animal models using zebrafish or Drosophila. Unbiased approaches in small animal models are used as hypothesis-generating models. Identified modifiers are validated in small animal, cellular, and mouse models, as well as in patient-specific iPSC-derived neuronal cultures or other patient-derived materials.

Some of the targets we currently study in different forms of ALS and FTLD include the Ephrin receptor EphA4, the elongator protein ELP3, the histone deacetylase HDAC6, and the growth factor progranulin. This translational approach aims to identify and develop novel therapeutics targets for these at present incurable diseases.

augustine tx

Hereditary motor neuropathies

Axonal degeneration of the motor axon is the main characteristic of Charcot-Marie-Tooth disease and of distal hereditary motor neuropathy (distal HMN). The laboratory also focuses on the pathogenic mechanisms underlying these diseases, with a particular focus on HSPB1 and GARS. The research concentrates on the involvement of cytoskeletal modifications (and in particular alpha-tubulin acetylation) in the pathogenesis of these peripheral neuropathies. Also for this disease, the lab uses iPSC-derived motor neuron model to investigate disease mechanisms.  

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Stroke

Stroke is a very common disease which leads to a massive burden of disability in society and causes approximately ten percent of all deaths. Ischemic stroke is the most common subtype followed by intracerebral hemorrhage and subarachnoid hemorrhage. Ischemic stroke is caused by obstruction of blood vessels by clot. These clots can originate in the heart, in vessels leading to the brain (aorta, cervical vessels) and in blood vessels within the brain. Leading causes of emboli are atrial fibrillation and carotid atherosclerosis. Few therapies are effective in the acute stage, except tissue plasminogen activator.