Neurite Aggregation and Calcium Dysfunction in iPSC-Derived Sensory Neurons with Parkinson’s Disease-Related LRRK2 G2019S Mutation

Abstract

SummaryMutations in leucine-rich repeat kinase 2 (LRRK2) are the most-common genetic determinants of Parkinson’s disease (PD). The G2019S mutation is detected most frequently and is associated with increased kinase activity. Whereas G2019S mutant dopamine neurons exhibit neurite elongation deficits, the effect of G2019S on other neuronal subtypes is unknown. As PD patients also suffer from non-motor symptoms that may be unrelated to dopamine neuron loss, we used induced pluripotent stem cells (iPSCs) to assess morphological and functional properties of peripheral sensory neurons. LRRK2 G2019S iPSC-derived sensory neurons exhibited normal neurite length but had large microtubule-containing neurite aggregations. Additionally, LRRK2 G2019S iPSC-derived sensory neurons displayed altered calcium dynamics. Treatment with LRRK2 kinase inhibitors resulted in significant, but not complete, morphological and functional rescue. These data indicate a role for LRRK2 kinase activity in sensory neuron structure and function, which when disrupted, may lead to sensory neuron deficits in PD.

Induced pluripotent stem cell‐based modeling of mutant LRRK2‐associated Parkinson's disease

“…A study by Reinhardt et al. revealed elevated levels of total‐tau and p‐tau in LRRK2 G2019S mesDA‐neurons compared to isogenic controls (Reinhardt, Schmid et al., ), and a similar observation was made in sensory neurons carrying the G2019S variant (Schwab & Ebert, ). Interestingly, in the same study, the authors did not observe accumulation of tau or p‐tau in an SNCA trp patient (Schwab & Ebert, ).…”

“…Consequently, several studies focused on the analysis of neurite length and complexity of mesDA neuronal cultures. It was shown by independent studies that neurite length and complexity are significantly reduced in LRRK2 G2019S mesDA neurons (Borgs et al, 2016;Lin et al, 2016;Sanchez-Danes et al, 2012;Schwab & Ebert, 2015;Su & Qi, 2013). Reinhardt and colleagues demonstrated a reduced neurite outgrowth velocity of LRRK2 G2019S mesDA neuronal cultures which could be rescued by continuous treatment with the LRRK2 kinase inhibitor-1 (IN-1) or ERK inhibitor (Reinhardt, Schmid et al, 2013).…”

Convergent pathways in Parkinson’s disease

“…Defects in Ca 2+ -buffering capacity are also evident in neurons expressing mutant LRRK2. Several studies support a role for LRRK2 in Ca 2+ signaling and homeostasis, reporting that mutated forms of the kinase protein generate altered calcium levels along with aberrations in mitochondrial degradation, dendrite shortening and neurite aggregation (Cherra et al 2013; Schwab and Ebert 2015). In line with this, it has been recently demonstrated that LRRK2 can impact Cav channel function, especially Cav of type 2 (Bedford et al 2016).…”

Current Opinion on the Role of Neurogenesis in the Therapeutic Strategies for Alzheimer Disease, Parkinson Disease, and Ischemic Stroke; Considering Neuronal Voiding Function

“…Although the underlying pathogenesis of PD remains poorly understood, increased LRRK2 kinase activity, which is caused by the G2019S mutation, is thought to be associated with LRRK2-linked PD [64] (Fig. 4).…”