My lab is interested in genes and molecular programs that are associated with movement disorders. We are using molecular and biochemical techniques in addition to mouse genetics and behavioral analyses to examine genes that are implicated in developmental and neurodegenerative disorders such as ataxias and parkinsonism. Increasing evidence accentuates the importance of the ubiquitin proteasome system (UPS) in these disorders. While the UPS is responsible for the proper clearance of worn out and unwanted proteins, it is also critically involved in signaling events in cells. Hence, we are interested in how the UPS contributes to the development and degeneration of the brain.

In one of our projects, we examine the function of UPS in cerebellar development and thus the molecular underpinnings of ataxias. We have developed a mouse model, in which the FBXO41 gene has been deleted. The mice display ataxic features and are characterized by a delay in neuronal migration in the developing cerebellum in addition to neurodegeneration in the adult cerebellum (Fig 1),1. In further studies, we will explore the molecular pathways regulated by the central nervous system-specific E3 ubiquitin ligase FBXO41 and the implication of these pathways in ataxias.


Another project deals with the PARK15 gene, which has been associated with a juvenile form of parkinsonism the so-called Parkinsonian-Pyramidal syndrome (PPS) 2-6. PARK15 encodes the E3 ubiquitin ligase FBXO7, whose role in neurons is largely unknown. Our aims are to determine the relevance of FBXO7 in the brain using conditional knock out mice (Fig 2). In addition, we will investigate which cellular systems are regulated by FBXO7 in neurons.



1 Mukherjee C, Holubowska A, Schwedhelm-Domeyer N et al. Loss of the Neuron-Specific F-Box Protein FBXO41 Models an Ataxia-Like Phenotype in Mice with Neuronal Migration Defects and Degeneration in the Cerebellum. J Neurosci 2015; 35:8701-8717.

2 Di Fonzo A, Dekker MC, Montagna P et al. FBXO7 mutations cause autosomal recessive, early-onset parkinsonian-pyramidal syndrome. Neurology 2009; 72:240-245.

3 Yalcin-Cakmakli G, Olgiati S, Quadri M et al. A new Turkish family with homozygous FBXO7 truncating mutation and juvenile atypical parkinsonism. Parkinsonism Relat Disord 2014; 20:1248-1252.

4 Shojaee S, Sina F, Banihosseini SS et al. Genome-wide linkage analysis of a Parkinsonian-pyramidal syndrome pedigree by 500 K SNP arrays. Am J Hum Genet 2008; 82:1375-1384.

5 Paisan-Ruiz C, Guevara R, Federoff M et al. Early-onset L-dopa-responsive parkinsonism with pyramidal signs due to ATP13A2, PLA2G6, FBXO7 and spatacsin mutations. Mov Disord 2010.

6 Lohmann E, Coquel AS, Honore A et al. A new F-box protein 7 gene mutation causing typical Parkinson's disease. Mov Disord 2015; 30:1130-1133.