α-Synuclein-induced dysregulation of neuronal activity contributes to murine dopamine neuron vulnerability

Abstract

Pathophysiological damages and loss of function of dopamine neurons precede their demise and contribute to the early phases of Parkinson’s disease. The presence of aberrant intracellular pathological inclusions of the protein α-synuclein within ventral midbrain dopaminergic neurons is one of the cardinal features of Parkinson’s disease. We employed molecular biology, electrophysiology, and live-cell imaging to investigate how excessive α-synuclein expression alters multiple characteristics of dopaminergic neuronal dynamics and dopamine transmission in cultured dopamine neurons conditionally expressing GCaMP6f. We found that overexpression of α-synuclein in mouse (male and female) dopaminergic neurons altered neuronal firing properties, calcium dynamics, dopamine release, protein expression, and morphology. Moreover, prolonged exposure to the D2 receptor agonist, quinpirole, rescues many of the alterations induced by α-synuclein overexpression. These studies demonstrate that α-synuclein dysregulation of neuronal activity contributes to the vulnerability of dopaminergic neurons and that modulation of D2 receptor activity can ameliorate the pathophysiology. These findings provide mechanistic insights into the insidious changes in dopaminergic neuronal activity and neuronal loss that characterize Parkinson’s disease progression with significant therapeutic implications.

Morpho‐Functional Changes of Nigral Dopamine Neurons in an α‐Synuclein Model of Parkinson's Disease

“…Noteworthy, in line with the absence of other signs of degeneration, 23 the dendritic arbor of DA cells is preserved at an earlier time‐point (5‐month‐old Snca +/+ rats). Interestingly, a recent study in neuronal cultures of midbrain DA neurons also demonstrated that virally induced α‐syn–overexpressing neurons exhibit a lower degree of dendritic arborization compared with naive DA neurons 48 . Altogether, α‐syn–dependent somatodendritic alterations observed in aged Snca +/+ nigral DA neurons model the pathological changes of the DAergic system occurring in humans during PD progression 43,45‐47 and provide additional insights into the mechanisms by which α‐syn overload drives SNpc DA neurons' pathology.…”

Systemic inflammation accelerates neurodegeneration in a rat model of Parkinson’s disease overexpressing human alpha synuclein

“…Another important feature highlighted in the present study is the dystrophic TH + dendritic arborizations, branching from SNpc surviving DAergic neurons towards the SNpr in LPS Snca +/+ rats, anticipating by almost seven months similar alterations in the naϊve Snca +/+ animals 21 . The loss of neuronal complexity and the decreased dendritic arborization have been linked to α-synuclein overexpression in virally infected DAergic neurons in vitro and in vivo , preceding their eventual death 34,35 and resembling PD patient’s post- mortem alterations 36 .…”

Diverging Parkinson’s Disease Pathology between patient-derivedGBAN370S, LRRK2G2019Sand engineeredSNCAA53TiPSC-derived Dopaminergic Neurons

“…Our data showing dysregulation of dopamine release and genes related to dopamine synthesis suggests a possible association with α-Syn accumulation and calcium homeostasis. Overexpression of α-Syn has been shown to decrease the auto-inhibitory function of D2 receptors in DA neurons and increase intracellular and extracellular dopamine levels and tyrosine hydroxylase expression 53 . Furthermore, calcium has been shown to directly and indirectly increase α-Syn pathology [54][55][56] .…”