Abstract
Non-motor symptoms are common in Parkinson’s disease (PD) and they represent a major source of disease burden. Several non-motor manifestations, such as rapid eye movement sleep behavior disorder, olfactory loss, gastrointestinal abnormalities, visual alterations, cognitive and mood disorders, are known to precede the onset of motor signs. Nonetheless, the mechanisms mediating these alterations are poorly understood and probably involve several neurotransmitter systems. The dysregulation of GABAergic system has received little attention in PD, although the spectrum of non-motor symptoms might be linked to this pathway. This Mini Review aims to provide up-to-date information about the involvement of the GABAergic system for explaining non-motor manifestations in early stages of PD. Therefore, special attention is paid to the clinical data derived from patients with isolated REM sleep behavior disorder or drug-naïve patients with PD, as they represent prodromal and early stages of the disease, respectively. This, in combination with animal studies, might help us to understand how the disturbance of the GABAergic system is related to non-motor manifestations of PD.
Highlights
Parkinson’s disease (PD) is the second most common neurodegenerative disorder with a prevalence of between 1% and 4% in over-60-year-olds (Tysnes and Storstein, 2017)
We report evidence consistent with the view that the GABAergic system is altered in PD and may contribute to non-motor symptoms that appear early in disease progression
Preclinical studies show the relevance of interneurons in odor detection and the causal role of GABA in anxiety and depressive disorders, but we are far from establishing whether this occurs in PD
Summary
Parkinson’s disease (PD) is the second most common neurodegenerative disorder with a prevalence of between 1% and 4% in over-60-year-olds (Tysnes and Storstein, 2017). GABA and Non-Motor PD Manifestations staging system, which suggests that α-synuclein deposition starts in areas involved in sleep regulation, olfaction or autonomic function before affecting the basal ganglia or cerebral cortex (Braak et al, 2003). Considering that GABAergic networks regulate calcium-mediated mechanisms, like mitochondrial function and oxidative stress, loss of GABA inhibitory tone would facilitate accumulation of abnormal levels of intracellular calcium, triggering neurodegenerative processes. Consistent with this idea, it has been shown that GABA agonists, such as Baclofen or Bumetadine, relieve motor symptoms and protect dopaminergic cell bodies in mice models of PD (Hajj et al, 2015; Lozovaya et al, 2018). Seeking to provide up-to-date information about the role of the GABAergic system, in this Mini Review, we focus on its ability to explain some of the non-motor manifestations that appear early in PD (Table 1)
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