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

Abstract

Interneuronal transfer and brain spreading of pathogenic proteins are features of neurodegenerative diseases. Pathophysiological conditions and mechanisms affecting this spreading remain poorly understood. This study investigated the relationship between neuronal activity and interneuronal transfer of α-synuclein, a Parkinson-associated protein, and elucidated mechanisms underlying this relationship. In a mouse model of α-synuclein brain spreading, hyperactivity augmented and hypoactivity attenuated protein transfer. Important features of neuronal hyperactivity reported here were an exacerbation of oxidative and nitrative reactions, pronounced accumulation of nitrated α-synuclein, and increased protein aggregation. Data also pointed to mitochondria as key targets and likely sources of reactive oxygen and nitrogen species within hyperactive neurons. Rescue experiments designed to counteract the increased burden of reactive oxygen species reversed hyperactivity-induced α-synuclein nitration, aggregation, and interneuronal transfer, providing first evidence of a causal link between these pathological effects of neuronal stimulation and indicating a mechanistic role of oxidant stress in hyperactivity-induced α-synuclein spreading.

Overexpression-Induced α-Synuclein Brain Spreading

“…A separate recent study provided further evidence of oxidant stress as a mechanism promoting α-synuclein pathology in the vagal model [50]. As described above, this pathology is markedly affected by neuronal activity, with hyperactivity enhancing both hα-synuclein aggregation and spreading.…”

“…Results revealed that, in the presence of enhanced SOD2, hyperactivityinduced oxidative burden was significantly alleviated. As importantly, SOD2 transduction completely reversed the pathological effects of neuronal stimulation on α-synuclein aggregation and interneuronal transfer, providing compelling evidence of a mechanistic link between hyperactivity, oxidant stress and α-synuclein pathology [50].…”

“…In a final set of experiments, the effect of neuronal activity was also evaluated in relation to other pathological features of the vagal model, in particular the aggregation of α-synuclein triggered by its enhanced neuronal expression. Results of these experiments revealed that, besides enhancing protein transfer, neuronal hyperactivity significantly exacerbated intraneuronal aggregate pathology [50].…”

“…Therefore, after establishing that cell integrity was essential for protein spreading under conditions of increased α-synuclein expression, another important question concerned the possibility that neuronal hyper-or hypoactivity may promote or, vice versa, suppress caudo-rostral α-synuclein advancement in the vagal model. This question was addressed in a study in which protein transduction within vagus-associated neurons was induced in conditional transgenic mice expressing hα-synuclein in a Cre recombinase-dependent manner [50]. When these animals were injected intravagally with AAVs carrying Cre recombinase DNA, targeted transgene expression was observed in the dorsal medulla oblongata.…”

“…The intravagal route was also used for injections of AAVs delivering DREADD (designer receptors exclusively activated by designer drugs) DNAs, in particular Gq-coupled hM3D DNA or Gi-coupled hM4D DNA [51,52]. Targeted expression of either of these two DREADDS and systemic administration of the synthetic ligand clozapine-N-oxide (CNO) resulted in enhanced (hM3D) or suppressed (hM4D) activity of DMnX neurons [50].…”