Understanding Microglial phagocytosis in PD pathogenesis: From mechanisms to therapy

Investigators: Alvin Joselin, David Park

Of the various genes that have been linked to PD, the autosomal dominantly transmitted LRRK2 gene is of particular interest, not just because it is the most frequently mutated, but also G2019S LRRK2 mutation is estimated to account for 1% of all sporadic and 4% familial PD worldwide. This raises the exciting possibility that the molecular mechanism of LRRK2 dysfunction is likely similar in familial and idiopathic PD. Initial preclinical studies using LRRK2 kinase inhibitors were suggestive of a protective effect but the mechanistic insights into these protective affects are lacking largely because the biological functions of LRRK2 are not well established.

There has been considerable interest in the role of LRRK2 in immune regulation. LRRK2 expression is predominantly neuronal with increased expression seen in activated monocytes and macrophages. Intriguingly, microglial activation and neuroinflammation are both strongly associated with PD. Our previous work has shown that in PD patients with LRRK2 mutations, phagocytic function is elevated and this enhancement in phagocytic activity affects DA neuron death in PD. Building on this knowledge, we are exploring two independent but closely linked investigations that:

  1. Explore the neuronal contribution of LRRK2 mediated cellular events that impact neuron-microglial crosstalk in LRRK2 G2019S rodent models.
  2. Identify pharmacological inhibitors of microglial phagocytosis using a high content cell-based screen of small molecule inhibitors from a library of 1040 drugs of particular importance to neurological disorders and stroke. 

The examination of phagocytosis status in idiopathic PD patients, understanding of the molecular mechanism impacted in LRRK2 rodent models and pharmacological inhibitors of phagocytosis identified through the proposed study will provide crucial insights into how this specific mode of immune modulation may be impacted and how this may be exploited for PD therapy.