Format

Send to

Choose Destination
Acta Neuropathol. 2019 Jun;137(6):961-980. doi: 10.1007/s00401-019-01995-0. Epub 2019 Mar 29.

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

Author information

1
Department of Genetics, Stanford University School of Medicine, 300 Pasteur Drive, M322 Alway Building, Stanford, CA, 94305-5120, USA.
2
Stanford Neurosciences Graduate Program, Stanford University School of Medicine, Stanford, CA, USA.
3
Institut François Jacob, MIRCen, CEA and Laboratory of Neurodegenerative Diseases, CNRS, Fontenay-aux-Roses, France.
4
Stanford Behavioral and Functional Neuroscience Laboratory, Stanford University, Stanford, CA, USA.
5
Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USA.
6
Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
7
Department of Genetics, Stanford University School of Medicine, 300 Pasteur Drive, M322 Alway Building, Stanford, CA, 94305-5120, USA. agitler@stanford.edu.
8
Stanford Neurosciences Graduate Program, Stanford University School of Medicine, Stanford, CA, USA. agitler@stanford.edu.

Abstract

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.

KEYWORDS:

Aggregation; Alpha-synuclein; GBA; Genetic interaction; LRRK2; Parkinson’s disease

Supplemental Content

Full text links

Icon for Springer Icon for PubMed Central
Loading ...
Support Center