Beyond Just Connectivity — Neuronal Activity Drives α‐Synuclein Pathology

Abstract

A defining feature of Parkinson’s disease (PD) is the appearance of proteinaceous α-synuclein (αSYN)–laden inclusions — so-called Lewy pathology (LP) — in neurons. One of the most popular theories about the origins of LP in the brain is that it arises from misfolded oligomeric or fibrillar forms of αSYN that have propagated in a prion-like fashion from either the olfactory bulb or the gut. This hypothesis has gained considerable steam in the last decade, based largely on the ability of synthetic preformed αSYN fibrils (PFFs) injected into the mouse striatum, olfactory bulb, or gut to propagate to synaptically connected structures. Because endogenous αSYN is recruited to intracellular aggregates and is necessary to spread pathology, this process has been called prion-like. Although there are similarities between prions and pathological forms of αSYN, there also seem to be significant differences. Through late PD stages, LP (and neuronal loss) is found in a few discrete brain locations, primarily in the brain stem and mesencephalon. Even a cursory consideration of the synaptic connectome of regions manifesting LP makes it clear that spreading is following some set of rules other than just whether neurons are synaptically connected. For example, the locus coeruleus is one of the earliest brain stem structures to manifest LP in PD patients. Yet one of its major sources of afferent input — the cerebellum — remains essentially free of LP in PD. Indeed, several recent rodent studies correlating neuronal connectivity maps with the distribution of S129 phosphorylated αSYN following stereotaxic injection of αSYN PFFs into the rodent brain suggest that although synaptic connections constrain propagation, they are not the whole story. There must be other factors in addition to synaptic connections that govern the spread of αSYN pathology in the human brain. The study by Ueda et al in this issue of Movement Disorders provides compelling evidence that regenerative activity is one of the factors that dictate spreading of PFFinduced αSYN pathology. Using an elegant combination of in vitro and in vivo approaches, the authors show that excitatory synaptic transmission and, by inference, spiking significantly increase uptake of αSYN-preformed fibrils (PFFs) — the first step in the propagation cascade. Using hippocampal neuronal cultures, the authors demonstrated that the noncompetitive α-amino-3-hydroxy-5-methyl4-isoxazolepropionic acid (AMPA) glutamate receptor antagonist perampanel attenuated PFF-induced elevation of S129 phosphorylated αSYN aggregates in neurons. This effect was mimicked by a competitive AMPA receptor antagonist or by blocking voltage-dependent Na+ channels with tetrodotoxin — arguing that it was excitation and spiking promoting PFF uptake. Next, using a pH-sensitive tag on PFFs, they showed that αSYN fibrils were being taken up into an acidic endosomal compartment. In agreement with previous work implicating fluidphase endocytosis or micropinocytosis in PFF uptake, the movement of extracellular PFFs in the cultures was reduced by Na/H transport inhibitor 5-(N-ethyl-N-isopropyl) amiloride. This observation is also consistent with the activity dependence of this form of endocytosis. Next, the authors moved to a mouse model and found that oral administration of perampanel before the injection of PFFs into the olfactory bulb significantly lowered the level of S129 phosphorylated αSYN aggregates 2 weeks later. Interestingly, oral administration of perampanel after PPF injection had little or no effect on the resulting αSYN pathology. PFF uptake’s activity dependence is a fundamental insight into how αSYN pathology might spread in the human brain. It is of considerable interest that most of the brain neurons that manifest LP in PD are spontaneously © 2021 International Parkinson and Movement Disorder Society