Table 1.

Examples for compensatory mechanisms categories in PD.

(A) Striatum localized mechanisms that maximize the effect of the remaining dopamine in this region, pre- and post-synaptic
1. Upregulation of enzymes involved in dopamine metabolism [such as tyrosine hydroxylase (TH) or aromatic acid decarboxylase (AADC)] in order to increase dopamine synthesis in the residual neurons	(60–62)
2. Upregulation of DRD2 expression on striatal neurons (augmenting responsiveness to the remaining dopamine)	(63–65)
3. Downregulation of the dopamine transporter (DAT), which leads to decreased dopamine reuptake and higher concentration in the synaptic cleft	(62, 66, 67)
4. Increase in the number of intrinsic striatal tyrosine hydroxylase (TH) interneurons	(68–70)
(B) Compensatory mechanisms located outside the striatum, and linked to modulation of basal ganglia direct and indirect pathways
Reduction of globus pallidus externa inhibition by the indirect pathway, reducing PD symptom severity. This might be mediated by several neurotransmitter systems, which reduce activity of the indirect pathway (for example, enkephalins)	(58, 71)
(C) Compensatory mechanisms positioned in brain regions and networks outside the basal ganglia but involved in motor system control
Increased activity of relevant cortical (e.g., supplementary motor area) and cerebellar regions (counterbalancing impaired basal ganglia function)	(72–74)