Mitochondrial Risk Factors in Parkinson's Disease

• Applicant: Privatdozent Manu Sharma, Ph.D.
• Subject Area: Molecular and Cellular Neurology and Neuropathology
• Term: from 2018 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 392376548

• Final Report Year: 2023

Final Report Abstract

Mitochondrial dysfunction has long been recognized as an early and causative event in PD pathogenesis. Earlier studies showed increased PD risk in subjects exposed to mitochondrial toxins followed by genetic studies unequivocally implicating early-onset forms of PD and mutations in distinct gene products (e.g. PINK1, Parkin) playing a major role in mitochondrial function and quality control. Interestingly, hallmarks of mitochondrial dysfunction have also been observed in cellular models established from sporadic PD patients, showing defective oxidative phosphorylation, increased oxidative stress, and mitochondrial DNA (mtDNA) damage. Neurodegeneration in such sporadic PD patients cannot be explained by aging or environmental factors alone, which possibly implies the existence of pathogenic variants in mitochondrial genes. This project aims to gain essential knowledge concerning the contribution of nuclear-encoded mitochondrial genes to the pathogenesis of PD via (i) elucidation of genetic risk variants, (ii) identification of mitochondrial phenotypes that contribute to PD pathogenesis, and (iii) analysis of their potential suitability as novel therapeutic targets. To disentangle the complex genetic architecture of PD, we investigated mitochondrial network perturbations in idiopathic PD (iPD) patients. To meet our objectives, we applied advanced computational modelling approaches and genotyping data from different worldwide consortia to identify mitochondrial risk factors potentially involved in PD pathogenesis. Importantly, newly discovered risk variants have been functionally validated in patient-based cellular models, allowing us to define specific mitochondrial pathways and phenotypes related to PD pathogenesis. This will help to dissect the heterogeneous group of iPD patients into pathogenic subtypes – in which the underlying neurodegeneration is due to a genetically defined mitochondrial burden – potentially eligible for future precision medicine therapeutic approaches.

Publications

• Understanding the role of genetic variability in LRRK2 in Indian population. Movement Disorders, 34(4), 496-505.
  Kishore, Asha; Ashok, Kumar Sreelatha Ashwin; Sturm, Marc; von‐Zweydorf, Felix; Pihlstrøm, Lasse; Raimondi, Francesco; Russell, Rob; Lichtner, Peter; Banerjee, Moinak; Krishnan, Syam; Rajan, Roopa; Puthenveedu, Divya Kalikavil; Chung, Sun Ju; Bauer, Peter; Riess, Olaf; Gloeckner, Christian Johannes; Kruger, Rejko; ... & Sharma, Manu
  
• Shared Genetics of Multiple System Atrophy and Inflammatory Bowel Disease. Movement Disorders, 36(2), 449-459.
  Shadrin, Alexey A.; Mucha, Sören; Ellinghaus, David; Makarious, Mary B.; Blauwendraat, Cornelis; Sreelatha, Ashwin A.K.; Heras‐Garvin, Antonio; Ding, Jinhui; Hammer, Monia; Foubert‐Samier, Alexandra; Meissner, Wassilios G.; Rascol, Olivier; Pavy‐Le, Traon Anne; Frei, Oleksandr; O'Connell, Kevin S.; Bahrami, Shahram; Schreiber, Stefan; Lieb, Wolfgang; Müller‐Nurasyid, Martina; ... & Sharma, Manu
  
• Replication of a Novel Parkinson's Locus in a European Ancestry Population. Movement Disorders, 36(7), 1689-1695.
  Grover, Sandeep; Kumar‐Sreelatha, Ashwin Ashok; Bobbili, Dheeraj R.; May, Patrick; Domenighetti, Cloé; Sugier, Pierre‐Emmanuel; Schulte, Claudia; Elbaz, Alexis; Krüger, Rejko; Gasser, Thomas & Sharma, Manu
  
• Dairy Intake and Parkinson's Disease: A Mendelian Randomization Study. Movement Disorders, 37(4), 857-864.
  Domenighetti, Cloé; Sugier, Pierre‐Emmanuel; Ashok, Kumar Sreelatha Ashwin; Schulte, Claudia; Grover, Sandeep; Mohamed, Océane; Portugal, Berta; May, Patrick; Bobbili, Dheeraj R.; Radivojkov‐Blagojevic, Milena; Lichtner, Peter; Singleton, Andrew B.; Hernandez, Dena G.; Edsall, Connor; Mellick, George D.; Zimprich, Alexander; Pirker, Walter; Rogaeva, Ekaterina; ... & Lang, Anthony E.
  
• Genome-wide Association and Meta-analysis of Age at Onset in Parkinson Disease. Neurology, 99(7).
  Grover, Sandeep; Kumar, Sreelatha Ashwin Ashok; Pihlstrom, Lasse; Domenighetti, Cloé; Schulte, Claudia; Sugier, Pierre-Emmanuel; Radivojkov-Blagojevic, Milena; Lichtner, Peter; Mohamed, Océane; Portugal, Berta; Landoulsi, Zied; May, Patrick; Bobbili, Dheeraj; Edsall, Connor; Bartusch, Felix; Hanussek, Maximilian; Krüger, Jens; Hernandez, Dena G.; ... & Blauwendraat, Cornelis
  
• Mendelian Randomisation Study of Smoking, Alcohol, and Coffee Drinking in Relation to Parkinson’s Disease. Journal of Parkinson's Disease, 12(1), 267-282.
  Domenighetti, Cloé; Sugier, Pierre-Emmanuel; Sreelatha, Ashwin Ashok Kumar; Schulte, Claudia; Grover, Sandeep; Mohamed, Océane; Portugal, Berta; May, Patrick; Bobbili, Dheeraj R.; Radivojkov-Blagojevic, Milena; Lichtner, Peter; Singleton, Andrew B.; Hernandez, Dena G.; Edsall, Connor; Mellick, George D.; Zimprich, Alexander; Pirker, Walter; Rogaeva, Ekaterina; ... & Elbaz, Alexis
  
• Sleep, Pain, and Neurodegeneration: A Mendelian Randomization Study. Frontiers in Neurology, 13 (2022, 5, 2).
  Grover, Sandeep & Sharma, Manu
  
• The Interaction betweenHLA‐DRB1and Smoking in Parkinson's Disease Revisited. Movement Disorders, 37(9), 1929-1937.
  Domenighetti, Cloé; Douillard, Venceslas; Sugier, Pierre‐Emmanuel; Sreelatha, Ashwin Ashok Kumar; Schulte, Claudia; Grover, Sandeep; May, Patrick; Bobbili, Dheeraj R.; Radivojkov‐Blagojevic, Milena; Lichtner, Peter; Singleton, Andrew B.; Hernandez, Dena G.; Edsall, Connor; Gourraud, Pierre‐Antoine; Mellick, George D.; Zimprich, Alexander; Pirker, Walter; Rogaeva, Ekaterina; ... & Lang, Anthony E.
  
• What have we learned from genome-wide association studies (GWAS) in Parkinson's disease?. Ageing Research Reviews, 79, 101648.
  Fernández-Santiago, Rubén & Sharma, Manu