Mutant α-Synuclein Overexpression Induces Stressless Pacemaking in Vagal Motoneurons at Risk in Parkinson's Disease

Abstract

Overexpression of mutant α-synuclein causes Parkinson's disease, presumably by driving neurodegeneration in vulnerable neuronal target populations. However, the extent of α-synuclein pathology (e.g., Lewy bodies) is not directly related to the degree of neurodegeneration across various vulnerable neuronal populations. Here, we show that, in contrast to dopamine neurons in the substantia nigra, vagal motoneurons do not enhance their excitability and oxidative load in response to chronic mutant α-synuclein overexpression. Rather, by downregulating their voltage-activated calcium channels, vagal motoneurons acquire a stressless form of pacemaking that diminishes mitochondrial and cytosolic oxidative stress. Emulating this endogenous adaptive response to α-synuclein overexpression could lead to novel strategies to protect dopamine neurons and perhaps delay the onset of Parkinson's disease.

α-Synuclein-induced Kv4 channelopathy in mouse vagal motoneurons causes non-motor parkinsonian symptoms

“…To address this, we measured voltage activated Ca 2+ (Cav) currents. We found that the total Cav currents in DMV neurons were reduced (data not shown), as shown previously in transgenic mice overexpressing human A53T a-synuclein (Lasser-Katz et al, 2017). Intriguingly, the reduction in Cav currents of DMV neurons in the AAV-A53T-transfected mice matched the reduction in their surface area.…”

“…We have shown previously that DMV neurons in transgenic mice that globally overexpresses human A53T a-synuclein undergo cell-autonomous adaptations (compared with control mice) in the form of a transcriptional downregulation of Cav currents, which leads to lower basal mitochondrial oxidative stress (Lasser-Katz et al, 2017). In the current, adult onset brain stem-selective a-synucleinopathy model, we replicated the reduction in total Cav current.…”

“…Similarly, measures of other electrophysiological properties of the DMV pacemaking (e.g., action potential threshold, width and afterhyperpolarization) were largely unaffected ( Supplementary Fig. 3), ruling out significant changes to other voltage-activated channels involved in pacemaking (Cooper et al, 2015;Goldberg et al, 2012;Lasser-Katz et al, 2017). Taken together, these findings suggest that the A53T-induced Kv4 channelopathy in DMV neurons is both selective and maladaptive.…”

“…In contrast to the strong evidence for neuroinflammation and cell loss in prodromal PD (Surmeier et al, 2017), we know nothing about functional changes in viable DMV neurons in humans and only very little in model systems (Thakur et al, 2019). In a global A53T-SNCA transgenic mouse model, we previously reported in vitro reductions in activity-dependent calcium loading and oxidative impairment of Kv4 channels in DMV neurons (Lasser-Katz et al, 2017). In contrast, global transgenic expression of mutant a-synuclein led to in vivo and in vitro hyperexcitability with Kv4 dysfunction in dopamine substantia nigra neurons (Subramaniam et al, 2014).…”

Cholinergic Interneurons Amplify Corticostriatal Synaptic Responses in the Q175 Model of Huntington’s Disease

“…Boxplots represent range (whiskers), median (thick bar) and lower and upper quartiles. In the current-voltage and current-LED intensity curves the medians of each measurement are presented with confidence intervals given by the 50% × (1 ± 1/√ n ) percentiles, where n is the sample size (Lasser-Katz et al, in press). The parametric ANCOVA test was used to test significant changes in these curves.…”