Mice Lacking α-Synuclein Display Functional Deficits in the Nigrostriatal Dopamine System

Abstract

alpha-Synuclein (alpha-Syn) is a 14 kDa protein of unknown function that has been implicated in the pathophysiology of Parkinson's disease (PD). Here, we show that alpha-Syn-/- mice are viable and fertile, exhibit intact brain architecture, and possess a normal complement of dopaminergic cell bodies, fibers, and synapses. Nigrostriatal terminals of alpha-Syn-/- mice display a standard pattern of dopamine (DA) discharge and reuptake in response to simple electrical stimulation. However, they exhibit an increased release with paired stimuli that can be mimicked by elevated Ca2+. Concurrent with the altered DA release, alpha-Syn-/- mice display a reduction in striatal DA and an attenuation of DA-dependent locomotor response to amphetamine. These findings support the hypothesis that alpha-Syn is an essential presynaptic, activity-dependent negative regulator of DA neurotransmission.

α-Synuclein – Regulator of Exocytosis, Endocytosis, or Both?

“…What is happening upon a-synuclein knockout? Here studies report decreased exocytosis [33,35,37,38], no change [36,39], or even increased exocytosis [40][41][42] (Table 2). However, these studies need to be interpreted with care because a-synuclein is not the only synuclein isoform, and loss of physiological function could possibly be compensated by b-or g-synuclein.…”

Revisiting oxidative stress and mitochondrial dysfunction in the pathogenesis of Parkinson disease—resemblance to the effect of amphetamine drugs of abuse

“…Although its physiological function is still unknown, it has been proposed to have a role in the integration of presynaptic signaling and neuronal plasticity [155].Prior findings are consistent with these roles, with alphaͲsyn appearing to control synaptic vesicle fusion and recycling. Most data indicate that alphaͲsyn inhibits synaptic transmission in an activityͲdependent manner, as observed in alphaͲsyn deficient mice, exhibiting accelerated recovery of dopaminerelease when presented to multiple stimuli [156]. In addition, alphaͲsyn is also predicted to have specific effects in dopaminergic neurons, where it may negatively regulate the activity of TH,as well as the activity of DAT [157].…”

Transcriptional dysregulation in a transgenic model of Parkinson disease

“…Familial PD cases have been linked to several genes, including α-synuclein (α-syn), a 140-amino-acid protein that may function in neurotransmitter release (Abeliovich et al, 2000;Murphy et al, 2000). Families with mutated α-syn exhibit autosomal dominant PD (Athanassiadou et al, 1999;Kruger et al, 1998;Polymeropoulos et al, 1997;Zarranz et al, 2004), and gene multiplication leading to increased wildtype α-syn levels also causes disease (Singleton et al, 2003).…”