Abstract
Degeneration of locus coeruleus (LC) neurons and dysregulation of noradrenergic signaling are ubiquitous features of Parkinson’s disease (PD). The LC is among the first brain regions affected by α-synuclein (asyn) pathology, yet how asyn affects these neurons remains unclear. LC-derived norepinephrine (NE) can stimulate neuroprotective mechanisms and modulate immune cells, while dysregulation of NE neurotransmission may exacerbate disease progression, particularly non-motor symptoms, and contribute to the chronic neuroinflammation associated with PD pathology. Although transgenic mice overexpressing asyn have previously been developed, transgene expression is usually driven by pan-neuronal promoters and thus has not been selectively targeted to LC neurons. Here we report a novel transgenic mouse expressing human wild-type asyn under control of the noradrenergic-specific dopamine β-hydroxylase promoter. These mice developed asyn aggregates in LC neurons, alterations in hippocampal and LC microglial abundance, upregulated GFAP expression, degeneration of LC fibers, decreased striatal dopamine metabolism, and age-dependent behaviors reminiscent of non-motor symptoms of PD. These mice provide novel insights into how asyn pathology affects LC neurons and how LC dysfunction may contribute to early PD pathophysiology.
Significance statement α-synuclein (asyn) pathology and loss of neurons in the locus coeruleus (LC) are two of the most ubiquitous neuropathologic features of Parkinson’s disease (PD). Dysregulated NE neurotransmission is associated with the non-motor symptoms of PD including sleep disturbance, emotional changes such as anxiety and depression, and cognitive decline. Importantly, loss of central NE may contribute to the chronic inflammation in, and progression of, PD. We have generated a novel transgenic mouse expressing human wild-type asyn in LC neurons to investigate how increased asyn expression affects the function of the central noradrenergic transmission and associated behaviors. We report cytotoxic effects of asyn overexpression associated with astrogliosis in the LC and LC target regions, degeneration of LC fibers with disruptions in striatal dopamine (DA) metabolism, and age-dependent alterations in non-motor behaviors.








