Abstract
Motor symptoms in Parkinson’s disease (PD) are tightly linked to the degeneration of substantia nigra dopaminergic neurons and their projections into the striatum. Moreover, a broad range of non-motor symptoms like anxiety and depression frequently occur in PD, most likely related to the loss of serotonergic neurons and their projections into corresponding target regions. Strikingly, nigral dopaminergic neurons and raphe serotonergic neurons are severely affected in PD showing characteristic hallmarks of PD neuropathology, in particular alpha-synuclein containing Lewy bodies and Lewy neurites. So far, the initial events underlying neurodegenerative processes in PD are not well understood. Several observations, however, indicate that neurites and synapses of diseased neurons may be the first subcellular compartments compromised by alpha-synuclein associated pathology. In particular axonal pathology and deficits in axonal transport may be leading to the onset of synucleinopathies such as PD. This review will highlight current findings derived from imaging and neuropathological studies in PD patients, as well as cellular and animal PD models, which define the initial underlying structural and molecular events within dopaminergic and serotonergic circuits leading to the ‘dying back’ degeneration of axonal projections in PD.
Highlights
Parkinson’s disease (PD) represents the second most common neurodegenerative disorder, affecting up to ten million people worldwide, with a predicted increase of more than twofold by 2030 (Dorsey et al, 2007)
Important functions are linked to the serotonergic system including motor function, as well as cognition and mood: Dysfunction of serotonin (5-hydroxytryptamine, 5-HT) neurotransmission contributes to resting tremor and levodopa-induced dyskinesias (Doder et al, 2003; Rylander et al, 2010; Politis et al, 2014) as well as to typical non-motor symptoms (NMS) of PD, in particular apathy, anxiety, anhedonia, and depression (Pavese et al, 2010; Ballanger et al, 2012)
Given the early appearance of NMS in PD and their tremendous impact on the patients’ quality of life it is important to compare the timeline of pathogenic events within the serotonergic system with those more soundly explored in the dopaminergic system
Summary
Parkinson’s disease (PD) represents the second most common neurodegenerative disorder, affecting up to ten million people worldwide (de Lau and Breteler, 2006), with a predicted increase of more than twofold by 2030 (Dorsey et al, 2007). Lewy pathology was described in numerous other neuronal subpopulations in distinct brain regions, most likely occurring even prior to dopaminergic SN neurons, e.g., in the medulla oblongata, olfactory bulb, and pontine tegmentum (Braak et al, 2003). These findings are paralleled by deficits of several neurotransmitter systems including serotonergic, noradrenergic, Axonal Degeneration in PD cholinergic, GABAergic, and glutamatergic signaling (reviewed in Brichta et al, 2013). Several studies imply that dysfunction of different neurotransmitter systems occur even prior to the presence of Lewy pathology and the consequent neuronal loss [e.g., reviewed in (Burke and O’Malley, 2013)]. This review will discuss recent findings of clinical and neuropathological studies, as well as molecular mechanisms from cellular and animal models supporting the concept of an early axonal pathology in PD
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