Early Degeneration of Both Dopaminergic and Serotonergic Axons – A Common Mechanism in Parkinson’s Disease

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.

Experimental Traumatic Brain Injury Induces Chronic Glutamatergic Dysfunction in Amygdala Circuitry Known to Regulate Anxiety-Like Behavior

“…Distance traveled between sham and braininjured rats did not reach significance as previously demonstrated in Liu et al in the same model at the same time point (Liu et al, 2017). While Liu et al (2017) reports dopamine axonal damage, 25% dopamine neuronal loss and microglia activation the nigrostriatal pathway, a minimum of 50% loss of substantia nigral dopamine neurons is associated with movement symptoms (Grosch et al, 2016), supporting that the loss of DA neurons is not the primary cause of decreased locomotor activity. Morris Water Maze testing at 15 DPI further provides evidence that injured rats were capable of swimming a similar distance at similar swim speed as shams indicating a behavioral response rather than an motor deficit (Clausen et al, 2017).…”

Nigrostriatal interaction in the aging brain: new therapeutic target for Parkinson’s disease

“…For instance, virtually all PD patients develop sleep disturbances at the early stage of the disease (Chaudhuri et al 2006). The disturbances have a multifactorial etiology, but early degeneration of the locus coeruleus noradrenergic system (Samuels and Szabadi 2008) and the serotonergic system related to the dorsal raphe nucleus (Grosch et al 2016) may be of particular importance for the pathology. Their dysfunctions result in a decline of the restorative function of sleep that may cause accumulation of potentially neurotoxic waste products within the CNS (Xie et al 2013).…”

The PERK-Dependent Molecular Mechanisms as a Novel Therapeutic Target for Neurodegenerative Diseases

“…Bradykinesia, resting tremor, postural instability, and muscular rigidity represent the specific symptoms of PD, which are connected with degeneration of DA neurons and thus result in neurotransmission failure within the nigrostriatal pathway [64,66,69]. Due to neural plasticity, it is estimated that a significant amount of DA neurons (approximately 30%) must have already been damaged by the time of the occurrence of the symptoms [66,70,71]. Other common extrapyramidal motor disturbances that have been noted among PD patients include muscle stiffness, motor blocks (freezing), akinesia, mask-like face expression, flexed posture, irregular arm swing, abnormal gait, and balance impairment [72,73].…”