α-Synuclein–induced Kv4 channelopathy in mouse vagal motoneurons drives nonmotor parkinsonian symptoms

Abstract

No disease-modifying therapy is currently available for Parkinson’s disease (PD), the second most common neurodegenerative disease. The long nonmotor prodromal phase of PD is a window of opportunity for early detection and intervention. However, we lack the pathophysiological understanding to develop selective biomarkers and interventions. By using a mutant α-synuclein selective-overexpression mouse model of prodromal PD, we identified a cell-autonomous selective Kv4 channelopathy in dorsal motor nucleus of the vagus (DMV) neurons. This functional remodeling of intact DMV neurons leads to impaired pacemaker function in vitro and in vivo, which, in turn, reduces gastrointestinal motility, a common early symptom of prodromal PD. We identify a chain of events from α-synuclein via a biophysical dysfunction of a specific neuronal population to a clinically relevant prodromal symptom. These findings will facilitate the rational design of clinical biomarkers to identify people at risk for developing PD.

Treating LRRK2‐Related Parkinson's Disease by Inhibiting the mTOR Signaling Pathway to Restore Autophagy

“…The results show that TVC can restore autophagy and eliminate the accumulation of abnormal proteins in vivo and in vitro, thereby playing a role in the treatment of PD. [ 30 ] According to further in‐depth analysis and discussion of the research results, we believe that TVC is a potential inhibitor of LRRK2 protein activation, which may inhibit the excessive activity of LRRK2 kinase by interfering with the conformation and dimerization of LRRK2 protein. Subsequently, the activation of the PI3K/Akt/mTOR signaling pathway was inhibited, which promoted the activation of the downstream autophagic flux and the formation of autophagosomes.…”

Neuronal hyperactivity–induced oxidant stress promotes in vivo α-synuclein brain spreading

“…Expression of synthetically designed receptors and binding of these receptors with specific ligands can be used for transient activation or inactivation of targeted brain regions ( 21 , 41 , 42 , 43 ). This DREADD approach has been successfully applied to induce hyper- or hypoactivity of DMnX neurons that was validated using electrophysiological recordings and functional outcomes ( 31 , 44 ). Experiments were carried out here to assess the effects of chemogenetically induced DMnX hyperactivity on h-αS brain transfer.…”

“…Expression and CNO-induced activation of the DREADD hM4D result in membrane hyperpolarization and suppression of neuronal activity ( 31 , 41 , 42 ). Experiments were therefore carried out using hM4D expression as a tool for assessing the effects of neuronal hypoactivity on h-αS nitration and h-αS spreading.…”

“…The vagus nerve can be used as a conduit for delivering viral vectors to the brain ( 27 , 31 , 39 , 40 , 52 ). In this study, Cre/ loxP conditional h-αS knock-in mice received an intravagal injection of Cre-AAVs to achieve stable expression of h-αS driven by the endogenous Rosa26 promoter.…”

Recovery of the fullin vivofiring range in post-lesion surviving DA SN neurons associated with Kv4.3-mediated pacemaker plasticity

“…Moreover, the results of this study imply that α-synuclein pathology interferes with the homeostatic capacity of surviving SN DA neurons, in particular the regulation of Kv4.3 channels. Indeed, we recently showed a Kv4.3 gain-of-function phenotype for vagal motoneurons in response to mutant SNCA expression (Chiu et al, 2021). Thus, Kv4.3 channels -a major "brake" of the pacemaker rate (Khaliq and Bean, 2008;Liss et al, 2001;Tarfa et al, 2017) -is an emerging downstream target across several PD models.…”