We are working on the cellular and molecular basis of neurological diseases with emphasis on Parkinson's disease and phosphoinositide metabolism.
Parkinson's disease is characterized by aggregation of alpha-synuclein in neuronal cells of the central and peripheral nervous systems. We have found that cells can sequester such protein aggregates in aggresomes and degrade them through autophagy. We now study the molecular basis of this clearance process in order to identify new molecular targets for the development of neuroprotective therapies.
The transport of aggregates into a perinuclear aggresome is mediated by the microtubule-dynein system. Lewy bodies are likely derived from to such aggresomes. We investigate the molecular components necessary for aggregate transport, in particular the molecules responsible for linking misfolded proteins to the dynein complex, and determine the rate-limiting resource for aggregate transport. We compare the transport of aggregates in neurons to transport in cell lines in order to determine the specific vulnerability of neuronal cells for protein aggregates.
Autophagy and Rab proteins
Degradation of aggregates is mediated by autophagy where pieces of cytosol are engulfed by a membrane. These autophagosomes subsequently fuse with lysosomes to degrade their content. We determine the molecular players and cellular trafficking events involved in autophagic aggregate clearance.
In previous work we could show that autolysosomal degradation of alpha-synuclein aggregates is induced by overexpression of Rab7. Several Rab proteins promote aggregate clearance, but Rab7 is of particular interest since it mediates effects of PINK, parkin and LRRK2 (mutations in these genes are associated with familial Parkinson's disease). The most important effector of Rab7 is FYCO1, which also induces aggregate clearance.
We are particularly interested in the intracellular trafficking route of autophagosomes and in the role membrane lipids for autophagosome maturation.
In order to further develop our previous work into a therapeutic strategy for Parkinson's disease we validate interventions found effective in cell lines in more advanced models. We test such interventions in primary mouse neurons, IPS-cell derived neurons, and in a mouse model using intracerebral injection of alpha-synuclein fibrils.
Plastic changes resulting from dopamine deficiency
Motor symptoms of Parkinson's disease result from degeneration of dopaminergic neurons of the substantia nigra, which results in dopamine deficiency in the striatum. We have identified secondary changes in striatal medium spiny neurons resulting from dopamine deficiency and now investigate the cell biological events that underlie these changes. We expect that preventing them can reduce dyskinesias and motor fluctuations that occur in advanced stages of PD.
Phosphoinositides are membrane lipids with important functions in signaling. We investigate the metabolism and functions of celluar phosphoinositides. While we have previously focused on plasma membrane receptors that alter phosphoinositides, we currently investigate intracellular and ciliary phosphoinositides.
All publications can be found on Pubmed
Link to Researchgate