| First Author | Henderson MX | Year | 2018 |
| Journal | Acta Neuropathol Commun | Volume | 6 |
| Issue | 1 | Pages | 45 |
| PubMed ID | 29855356 | Mgi Jnum | J:268923 |
| Mgi Id | MGI:6269003 | Doi | 10.1186/s40478-018-0550-0 |
| Citation | Henderson MX, et al. (2018) LRRK2 activity does not dramatically alter alpha-synuclein pathology in primary neurons. Acta Neuropathol Commun 6(1):45 |
| abstractText | Mutations in leucine-rich repeat kinase (LRRK2) are the most common cause of heritable Parkinson's disease (PD), and the most common mutations in LRRK2 lead to elevated kinase activity. For these reasons, inhibitors targeting LRRK2 have been the subject of intense research and development. However, it has been difficult to develop preclinical models that recapitulate PD-relevant LRRK2 phenotypes. The primary pathology in PD is the Lewy body (LB), which is a cytoplasmic aggregate of alpha-synuclein. The recent demonstration that LB-like aggregates of alpha-synuclein can be induced in primary neurons has provided a robust model for testing genetic modifiers of PD-relevant aggregation and neurodegeneration. In this study, we test the modulation of alpha-synuclein pathology by LRRK2 in primary neuron cultures using biochemistry and immunocytochemistry. We find that expression of familial mutant G2019S LRRK2 does not dramatically elevate the pathological burden of alpha-synuclein or neurodegeneration in neurons. We further test three LRRK2 inhibitors in two strains of wildtype neurons and find that even robust LRRK2 inhibition is insufficient to reduce alpha-synuclein pathology. LRRK2 inhibitors similarly had no effect in neurons with alpha-synuclein pathology seeded by human brain-derived pathological alpha-synuclein. Finally, we find that this lack of pathological modulation by LRRK2 was not confined to hippocampal neurons, but was also absent in midbrain dopaminergic neuron cultures. These data demonstrate that LRRK2 activity does not have more than minor effects on alpha-synuclein pathology in primary neurons, and more complex models may be needed to evaluate the ability of LRRK2 inhibitors to treat PD. |
