Mechanisms of neuronal degeneration in aging and disease

Lab Description

The work in my lab focuses on the generation and characterization of mouse models of neurodegenerative diseases. We generated several mouse models for amyotrophic lateral sclerosis and performed in depth neuropathological analyses on these mouse models. In SOD1-ALS mice we showed that pathological disease starts in motor neurons and subsequently in nearby neurons and astrocytes. We also found that neuronal expression of mutant SOD1 is sufficient to trigger disease (Jaarsma et al., 2008; Teuling et al., 2008; Kuijpers et al., 2013; van Dis et al., 2014). In VAPB-ALS mice we found that mutant VAPB in may accumulate in seemingly harmless abnormaly organised ER clusters in the center of Nissl bodies (Kuijpers, 2013).

In addition to proteinopathy mouse models for ALS, we have started to examine neurodegenerative changes in mice that are deficient in proteins of the nucleotide excision DNA-repair pathways and that model rare progeroid and UV-sensitivity disorders (de Waard et al., 2010; Borgesius et al., 2011; Jaarsma et al., 2011; Jaarsma et al., 2013; Barnhoorn et al., 2014). These experiments are performed in close collaboration with the Hoeijmakers lab. Following up on the finding that dietary restriction dramatically increases life span and reduces DNA damage and neurodegenerative changes in progeroid DNA repair-deficient mice (Vermeij et al., 2016), we are now zooming in on the question how dietary restriction attenuates neuronal degeneration in these progeroid mice. In addition, we are analyzing to which extent the neuroprotective effects of dietary restriction in repair-deficient mice explain the beneficial effect of dietary restriction in preventing neuronal aging.

A second line of research in the lab focusses on incompletely characterized aspects of the anatomy of the cerebellum. We recently showed that BIN neurons, a hitherto negelected population of neurons in the white matter of the vestibullocerebellum, are GABAergic neurons that innervate granule cells in the flocculus, and receive excitatory input from the medullary reticular formation (Jaarsma, 2018).