LRRK2 modifies α-syn pathology and spread in mouse models and human neurons

• Published in: Acta neuropathologica Vol. 137; no. 6; pp. 961 - 980
• Main Authors: Bieri, Gregor, Brahic, Michel, Bousset, Luc, Couthouis, Julien, Kramer, Nicholas J., Ma, Rosanna, Nakayama, Lisa, Monbureau, Marie, Defensor, Erwin, Schüle, Birgitt, Shamloo, Mehrdad, Melki, Ronald, Gitler, Aaron D.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.06.2019; Springer Nature B.V; Springer Verlag
• Subjects: alpha-Synuclein - metabolism; Amyloid - metabolism; Animal models; Animals; Basal ganglia; Biochemistry, Molecular Biology; Brain diseases; Cells, Cultured; Cellular Biology; Central nervous system diseases; Cerebral Cortex - cytology; Clinical trials; Dopamine receptors; Exploratory Behavior; Genetic screening; Glucosylceramidase - genetics; Hippocampus - cytology; Humans; Induced Pluripotent Stem Cells - cytology; Inflammation; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 - antagonists & inhibitors; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 - deficiency; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 - genetics; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 - physiology; Life Sciences; LRRK2 protein; Medicine; Medicine & Public Health; Mice; Mice, Inbred C57BL; Mice, Transgenic; Movement disorders; Mutation; Mutation, Missense; Neurodegeneration; Neurodegenerative diseases; Neurons; Neurons - metabolism; Neurons - pathology; Neurons and Cognition; Neurosciences; Original Paper; Parkinson Disease - genetics; Parkinson Disease - pathology; Parkinson's disease; Pars Compacta - pathology; Pathology; Pluripotency; Primary Cell Culture; Protein Aggregation, Pathological - etiology; Protein Aggregation, Pathological - genetics; Protein Aggregation, Pathological - pathology; Recombinant Proteins - metabolism; Risk factors; RNA Interference; Rotarod Performance Test; Stem cells; Substantia nigra; Synuclein; Therapeutic applications; Transgenic mice; Aggregation; Genetic interaction; LRRK2; Parkinson’s disease; Alpha-synuclein; GBA
• DOI: 10.1007/s00401-019-01995-0
• ISSN: 0001-6322; 1432-0533

Progressive aggregation of the protein alpha-synuclein (α-syn) and loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) are key histopathological hallmarks of Parkinson’s disease (PD). Accruing evidence suggests that α-syn pathology can propagate through neuronal circuits in the brain, contributing to the progressive nature of the disease. Thus, it is therapeutically pertinent to identify modifiers of α-syn transmission and aggregation as potential targets to slow down disease progression. A growing number of genetic mutations and risk factors has been identified in studies of familial and sporadic forms of PD. However, how these genes affect α-syn aggregation and pathological transmission, and whether they can be targeted for therapeutic interventions, remains unclear. We performed a targeted genetic screen of risk genes associated with PD and parkinsonism for modifiers of α-syn aggregation, using an α-syn preformed-fibril (PFF) induction assay. We found that decreased expression of Lrrk2 and Gba modulated α-syn aggregation in mouse primary neurons. Conversely, α-syn aggregation increased in primary neurons from mice expressing the PD-linked LRRK2 G2019S mutation. In vivo, using LRRK2 G2019S transgenic mice, we observed acceleration of α-syn aggregation and degeneration of dopaminergic neurons in the SNpc, exacerbated degeneration-associated neuroinflammation and behavioral deficits. To validate our findings in a human context, we established a novel human α-syn transmission model using induced pluripotent stem cell (iPS)-derived neurons (iNs), where human α-syn PFFs triggered aggregation of endogenous α-syn in a time-dependent manner. In PD subject-derived iNs, the G2019S mutation enhanced α-syn aggregation, whereas loss of LRRK2 decreased aggregation. Collectively, these findings establish a strong interaction between the PD risk gene LRRK2 and α-syn transmission across mouse and human models. Since clinical trials of LRRK2 inhibitors in PD are currently underway, our findings raise the possibility that these may be effective in PD broadly, beyond cases caused by LRRK2 mutations.