Biology subjects

Brahmia, B.

Publications and source records attributed to Brahmia, B..

2 recordsLinked to original sources

bioRxiv2024

Pathogenic LRRK2 causes age-dependent and region-specific deficits in ciliation, innervation and viability of cholinergic neurons

Pathogenic activating point mutations in the LRRK2 kinase cause autosomal-dominant familial Parkinso[n]s disease (PD). In cultured cells, mutant LRRK2 causes a deficit in de novo cilia formation and also impairs ciliary stability. In brain, previous studies have shown that in PD patients due to the G2019S-LRRK2 mutation as well as in middle-aged G2019S-LRRK2 knockin mice, striatal cholinergic interneurons show a deficit in primary cilia. Here, we show that cilia loss in G2019S-LRRK2 knockin mice is not limited to cholinergic striatal interneurons but common to cholinergic neurons across distinct brain nuclei. The lack of cilia in cholinergic forebrain neurons is accompanied by the accumulation of LRRK2-phosphorylated Rab12 GTPase and correlates with the presence of dystrophic cholinergic axons. Those deficits are already evident in young adult mutant LRRK2 mice. In contrast, the age-dependent loss of cilia in brainstem cholinergic neurons correlates with an age-dependent loss of cholinergic innervation derived from this brain area. Strikingly, we find cholinergic cell loss in mutant LRRK2 mice that is age-dependent, cell type-specific and disease-relevant. The age-dependent loss of a subset of cholinergic neurons mimics that observed in sporadic PD patients, highlighting the possibility that these particular neurons may require functional cilia for long-term cell survival.

neuroscience↗

bioRxiv2023

Targeting phosphoRab-RILPL Interactions as a Strategy to Downregulate Pathogenic LRRK2 in Parkinson's Disease

Familial Parkinsons disease (PD) is frequently linked to multiple disease-causing mutations within Leucine-Rich Repeat Protein Kinase 2 (LRRK2), leading to aberrant kinase activity. Multiple pathogenic effects of enhanced LRRK2 activity have been identified including loss of cilia and centrosomal cohesion defects. When phosphorylated by LRRK2, Rab8a and Rab10 bind to phospho-specific RILPL effector proteins. RILPL-mediated accumulation of pRabs proximal to the mother centriole is critical for initiating deficits in ciliogenesis and centrosome cohesion mediated by LRRK2. We hypothesized that Rab-derived phospho-mimics may serve to block phosphorylated Rab proteins from docking with RILPL in the context of hyperactive LRRK2 mutants. This would serve as an alternative strategy to downregulate pathogenic signaling mediated by LRRK2, rather than targeting LRRK2 kinase activity itself. To test this theory, we designed a series of constrained peptides mimicking phosphorylated Switch II derived from Rab8. These RILPL interacting peptides, termed RIP, were further shown to permeate cells. Further, several peptides were found to bind RILPL2 and restore ciliogenesis and centrosomal cohesion defects in cells expressing PD-associated mutant LRRK2. This research demonstrates the utility of constrained peptides as downstream inhibitors to target pathogenic LRRK2 activity and may provide an alternative approach to target specific pathways activated by LRRK2.

biochemistry↗