Deficits in dopaminergic transmission precede neuron loss and dysfunction in a new Parkinson model

Abstract

The pathological end-state of Parkinson disease is well described from postmortem tissue, but there remains a pressing need to define early functional changes to susceptible neurons and circuits. In particular, mechanisms underlying the vulnerability of the dopamine neurons of the substantia nigra pars compacta (SNc) and the importance of protein aggregation in driving the disease process remain to be determined. To better understand the sequence of events occurring in familial and sporadic Parkinson disease, we generated bacterial artificial chromosome transgenic mice (SNCA-OVX) that express wild-type α-synuclein from the complete human SNCA locus at disease-relevant levels and display a transgene expression profile that recapitulates that of endogenous α-synuclein. SNCA-OVX mice display age-dependent loss of nigrostriatal dopamine neurons and motor impairments characteristic of Parkinson disease. This phenotype is preceded by early deficits in dopamine release from terminals in the dorsal, but not ventral, striatum. Such neurotransmission deficits are not seen at either noradrenergic or serotoninergic terminals. Dopamine release deficits are associated with an altered distribution of vesicles in dopaminergic axons in the dorsal striatum. Aged SNCA-OVX mice exhibit reduced firing of SNc dopamine neurons in vivo measured by juxtacellular recording of neurochemically identified neurons. These progressive changes in vulnerable SNc neurons were observed independently of overt protein aggregation, suggesting neurophysiological changes precede, and are not driven by, aggregate formation. This longitudinal phenotyping strategy in SNCA-OVX mice thus provides insights into the region-specific neuronal disturbances preceding and accompanying Parkinson disease.dopamine transmission | in vivo electrophysiology | voltammetry | neurodegeneration | behavioral phenotyping T he development of new disease-modifying therapies for Parkinson disease (PD) is critically dependent on animal models that accurately recapitulate pathophysiological sequelae in an age-dependent manner. The generation of such models using genetically altered animals has proved challenging. The traditional use of heterologous gene promoters in the generation of transgenic mouse models precluded an endogenous transgene expression profile and produced additional phenotypes that are not characteristic of PD (1). In contrast, bacterial artificial chromosome (BAC) technology can enable expression of a desired transgene under the control of its native promoter and regulatory elements to achieve a correct spatiotemporal expression profile, thereby providing a more physiological model for investigating molecular mechanisms of the disease.The α-synuclein gene (SNCA) has been implicated in PD through three dominant point mutations (2-4) and locus multiplication (5, 6). SNCA duplications and triplications cause autosomal-dominant PD in which the age of onset and disease severity are related in a gene dosage-dependent manner (5, 6). More recently, genome-wide associatio...

α-Synuclein Mutation Inhibits Endocytosis at Mammalian Central Nerve Terminals

“…1H ). This result is consistent with a previous finding that ␣-syn mutations suppress transmitter release (Nemani et al, 2010;Lundblad et al, 2012;Janezic et al, 2013).…”

“…Consistently, we found that h-␣-syn A53T and h-␣-syn, but not h-␣-syn A30P , inhibited endocytosis. The lack of inhibitory effects of ␣-syn A30P might be due to its weaker membrane binding affinity than ␣-syn or ␣-syn A53T (Jo et al, 2002;Outeiro and Lindquist, 2003;Bussell and Eliezer, 2003). We could not exclude the possibility that the longer exposure of ␣-syn A30P in older mice inhibits endocytosis and exocytosis, considering that the ␣-syn A30P mutation is associated with late PD onset and incomplete penetrance (Krüger et al, 2001).…”

“…Before causing the progressive neuronal loss, ␣-syn mutations suppress the release of neurotransmitters and hormones at synapses and neuroendocrine cells (Kurz et al, 2010;Nemani et al, 2010;Scott et al, 2010;Lundblad et al, 2012;Janezic et al, 2013). Impairment of exocytosis represents the earliest defects in the progression toward PD (Nemani et al, 2010;Bendor et al, 2013), which may contribute to eventual neurodegeneration.…”

Cellular processes associated with LRRK2 function and dysfunction

“…It is the mechanism of LRRK2 associated with these events that needs to be uncovered. For example, LRRK2 has been associated with Wnt signalling pathways 76, which are essential for the acute regulation of synaptic function; a function that is dysregulated in the premotor symptom stages of rodent models of PD 180. From this prospective, the involvement of LRRK2 in Wnt signalling is an exciting possibility that may give a reason for the alteration in gene expression, as well as disruption of vesicle trafficking 181, which are implicated in PD.…”

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

“…Recent work in Parkinson's disease models with overexpression of wild-type a-synuclein show mainly an inhibitory effect of a-synuclein on neurotransmitter release [29][30][31][32][33][34], whereas two other studies come to the opposite conclusions [35,36]. In one of the latter increased synaptic activity was found in cultured hippocampal neurons acutely injected with a-synuclein.…”