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.
Highlights
Parkinson’s disease (PD) is characterized by a progressive loss of midbrain dopaminergic neurons in the substantia nigra pars compacta (SNpc), resulting in motor symptoms, including rigidity, postural instability, tremor at rest and bradykinesia [26, 34]
We demonstrated that abrogation of endogenous Lrrk2 in mouse primary neurons decreases α-syn aggregates, whereas expression of the familial PDassociated G2019S mutation increases aggregation
Transgenic mouse data demonstrated that expression of LRRK2 G2019S exacerbates α-syn aggregation, dopaminergic neuron degeneration, as well as associated neuroinflammatory and behavioral impairments in a preformed fibrils (PFFs)-based mouse model of PD
Summary
Parkinson’s disease (PD) is characterized by a progressive loss of midbrain dopaminergic neurons in the substantia nigra pars compacta (SNpc), resulting in motor symptoms, including rigidity, postural instability, tremor at rest and bradykinesia [26, 34]. Extended author information available on the last page of the article is the presence of intracellular protein aggregates termed Lewy bodies (LB), whose major component is the protein alpha-synuclein (α-syn) [18, 19, 25, 34]. A growing number of dominant and recessive genetic mutations, as well as genetic risk factors, have been identified in families with a high prevalence of PD (fPD), accounting for approximately 5–10% of all PD cases. Genome-wide association studies (GWAS) have identified additional genomic loci and candidate genes conferring risk for PD [11]. Rare mutations in SNCA, the gene encoding α-syn, as well as duplications and triplications of the locus haven been linked to PD— establishing a direct genetic link between PD and α-syn [4, 12, 35, 36, 50, 54, 64]
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