Molecular Mechanisms of Movement Disorders

Molecular mechanisms of movement disorders 
We are searching for genes involved in Parkinson’s disease (PD) and other movement disorders, to provide clues for understanding of the disease mechanisms, and to identify novel targets for the development of therapies to stop and prevent these diseases. PD is a common degenerative disease of the brain characterized by the progressive loss of dopaminergic neurons and the formation of neuronal inclusions (Lewy bodies) in the surviving neurons. The pathogenesis of PD remains mostly unknown, but a growing list of gene defects identified in the past few years in some inherited forms of the disease offers exciting opportunities to disentangle the complex molecular pathways leading to PD. 

Gene finding 
We use a number of unbiased strategies for the identification of novel genes causing or predisposing to PD and other movement disorders, such as dystonia. Our experimental approaches, coordinated by Andrea Conidi, include family-based linkage mapping, homozygosity mapping, next-generation sequencing (exome sequencing and whole genome sequencing), and in-silico analysis of large OMICs data (genomics, RNA-seq, proteomics). 

Functional studies 
Each of the Mendelian forms of disease might provide important new clues for understanding of the pathogenesis also in the more common, complex forms of the disease.  
We perform a number of functional studies, coordinated by Wim Mandemakers, aimed at the illumination of the normal function of the proteins encoded by the disease-causing gene(s), and understanding how the disease-causing variants lead to the neurodegeneration.  

In our endeavor, we currently use in-vitro models of disease based on induced pluripotent stem cells-derived neuronal and glial cell cultures and brain organoids made from skin cells donated from patients and unaffected controls, as well as unbiased brain and single-cell transcriptomics and proteomics. 

242 publications indexed in Pubmed

H-Index 70  (Scopus) 

Total number of citations: >22000 

Most cited work (Bonifati et al., Science 2003): >2400 citations


Selected references 

LRP10 and α-synuclein transmission in Lewy body diseases. 
Carreras Mascaro A, Grochowska MM, Boumeester V, Dits NFJ, Bilgiҫ EN, Breedveld GJ, Vergouw L, de Jong FJ, van Royen ME, Bonifati V, Mandemakers W. Cell Mol Life Sci 2024; 81: 75. 

 
PTPA variants and impaired PP2A activity in early-onset parkinsonism with intellectual disability.  
Fevga C, Tesson C, Carreras Mascaro A, Courtin T, van Coller R, Sakka S, Ferraro F, Farhat N, Bardien S, Damak M, Carr J, Ferrien M, Boumeester V, Hundscheid J, Grillenzoni N, Kessissoglou IA, Kuipers DJS, Quadri M; French and Mediterranean Parkinson disease Genetics Study Group; International Parkinsonism Genetics Network; Corvol JC, Mhiri C, Hassan BA, Breedveld GJ, Lesage S, Mandemakers W, Brice A, Bonifati V. Brain 2023; 146: 1496-1510. 

 
EIF2AK2 Missense Variants Associated with Early Onset Generalized Dystonia. 
Kuipers DJS, Mandemakers W, Lu CS, Olgiati S, Breedveld GJ, Fevga C, Tadic V, Carecchio M, Osterman B, Sagi-Dain L, Wu-Chou YH, Chen CC, Chang HC, Wu SL, Yeh TH, Weng YH, Elia AE, Panteghini C, Marotta N, Pauly MG, Kühn AA, Volkmann J, Lace B, Meijer IA, Kandaswamy K, Quadri M, Garavaglia B, Lohmann K, Bauer P, Mencacci NE, Lubbe SJ, Klein C, Bertoli-Avella AM, Bonifati V. Ann Neurol 2021; 89: 485-497. 

 
LRP10 interacts with SORL1 in the intracellular vesicle trafficking pathway in non-neuronal brain cells and localises to Lewy bodies in Parkinson's disease and dementia with Lewy bodies. 
Grochowska MM, Carreras Mascaro A, Boumeester V, Natale D, Breedveld GJ, Geut H, van Cappellen WA, Boon AJW, Kievit AJA, Sammler E; Netherlands Brain Bank; Parchi P, Cortelli P, Alessi DR, van de Berg WDJ, Bonifati V, Mandemakers W. Acta Neuropathol 2021; 142: 117-137. 

 
PTRHD1 Loss-of-function mutation in an african family with juvenile-onset Parkinsonism and intellectual disability. Kuipers DJS, Carr J, Bardien S, Thomas P, Sebate B, Breedveld GJ, van Minkelen R, Brouwer RWW, van Ijcken WFJ, van Slegtenhorst MA, Bonifati V, Quadri M. Movement Disorders 2018; 33: 1814-1819. 

DNAJC6 Mutations Associated With Early-Onset Parkinson's Disease. 
Olgiati S, Quadri M, Fang M, Rood JP, Saute JA, Chien HF, Bouwkamp CG, Graafland J, Minneboo M, Breedveld GJ, Zhang J; International Parkinsonism Genetics Network, Verheijen FW, Boon AJ, Kievit AJ, Jardim LB, Mandemakers W, Barbosa ER, Rieder CR, Leenders KL, Wang J, Bonifati V. Annals of Neurology 2016; 79: 244-56. 


Mutation in the SYNJ1 gene associated with autosomal recessive, early-onset parkinsonism. 
Quadri M, Fang M, Picillo M, Olgiati S, Breedveld GJ, Graafland J, Wu B, Xu F, Erro R, Amboni M, Pappatà S, Quarantelli M, Annesi G, Quattrone A, Chien HF, Barbosa ER; The International Parkinsonism Genetics Network, Oostra BA, Barone P, Wang J, Bonifati V. Human Mutation 2013; 34: 1208-15. 


Mutations in SLC30A10 cause parkinsonism and dystonia with hypermanganesemia, polycythemia, and chronic liver disease. 
Quadri M, Federico A, Zhao T, Breedveld GJ, Battisti C, Delnooz C, Severijnen LA, Di Toro Mammarella L, Mignarri A, Monti L, Sanna A, Lu P, Punzo F, Cossu G, Willemsen R, Rasi F, Oostra BA, van de Warrenburg BP, Bonifati V. American Journal of Human Genetics 2012; 90: 467-77. 


FBXO7 mutations cause autosomal recessive, early-onset parkinsonian-pyramidal syndrome.  
Di Fonzo A, Dekker MC, Montagna P, Baruzzi A, Yonova EH, Correia Guedes L, Szczerbinska A, Zhao T, Dubbel-Hulsman LO, Wouters CH, de Graaff E, Oyen WJ, Simons EJ, Breedveld GJ, Oostra BA, Horstink MW, Bonifati V. Neurology 2009; 72: 240-5. 


A frequent LRRK2 gene mutation associated with autosomal dominant Parkinson's disease.  
Di Fonzo A, Rohe CF, Ferreira J, Chien HF, Vacca L, Stocchi F, Guedes L, Fabrizio E, Manfredi M, Vanacore N, Goldwurm S, Breedveld G, Sampaio C, Meco G, Barbosa E, Oostra BA, Bonifati V. The Lancet 2005; 365: 412-415. 


Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism.  
Bonifati V, Rizzu P, van Baren MJ, Schaap O, Breedveld GJ, Krieger E, Dekker MC, Squitieri F, Ibanez P, Joosse M, van Dongen J, Vanacore N, van Swieten JC, Brice A, Meco G, van Duijn CM, Oostra BA, Heutink P. Science 2003; 299: 256-259. 

Department Neurology, iPCs core facility, Proteomic facility

We collaborate with a number of clinical partners (mostly neurologists) operating in several countries, for the study of large families with Mendelian neurodegenerative disease, other movement disorders, as well as case-control series, and genetically isolated populations.

Our research is supported by grants from:

• Stichting Parkinsonfonds.
• Alzheimer Nederland.