Pathobiology of Parkinson's disease associated genes

Abstract

Parkinson’s disease (PD) is pathologically defined by dopaminergic (DA) neuron loss and Lewy pathologies (LP) including Lewy bodies (LB) and neurites (LN) enriched with a-synuclein (a-syn). Genetic forms of PD have provided critical insights into PD pathogenesis and pathobiology, however, the impact of PD genetic mutations on cellular pathologies and comparisons across mutations is limited. LP types were assessed and compared in post-mortem cortical tissue from SNCA-mutation and sporadic PD (sPD) cases. sPD had mainly mature LBs whereas SNCA cases had equivalent solid and pale/mixed LBs and more neurons with puncta. sPD and E46K cases had a similar high proportion of RhoA+ LBs unlike A53T and G51D cases. Thus, LB formation and progression may differ between SNCA-related and sPD. To explore pathologies in other PD mutations, SNCA, LRRK2 and PRKN PD induced pluripotent stem cell-derived DA neuron transplants were assessed and compared. The quantity of DA neurons was similar across groups although the PRKN group had smaller neurons. Grafted DA neurons had similar a-syn and tau levels. Morphologically diverse phospho-a-syn/tau aggregate-like structures were seen in all grafts, however most were not or only partially localised to DA neurons. This suggests that the mutations produce similar early protein expression and structures which may be related to early LN formation or other developmental aspects. While all grafts exhibited aggregate-like structures, PRKN PD cases do not usually have LP prompting exploration on the impact of PRKN loss on pathologies in a PRKN knockout (KO) mouse model. While a-syn levels were unchanged, PRKN KO altered the levels of some mitochondrial proteins without altering neuronal/glial markers or activating microglia, suggesting that these mitochondrial changes may be insufficient to induce degeneration or inflammation. These findings provide novel insights into the impact of different PD genetic mutations on cellular pathologies.