Table 1.

Purinergic signaling in HD and PD.

	Expressed by (cell type)	Function in the CNS	Function in disease
A2A	Neurons, astrocytes, microglia, and oligodendrocytes [70, 72, 167].	Modulation of dopamine and glutamate neurotransmission, neuroinflammation, and synaptic plasticity [65, 71, 168].	HD: A2A receptor expression is downregulated in HD pathogenesis and A2A receptor activation might have beneficial effects HD rodent models [116–118, 120–122], but contradictory results suggest that A2A receptor antagonism improves the motor disease [124, 125].
			PD: Generally, antagonists of A2A receptors promote motor and cognitive recovery [169]. A selective A2A receptor antagonist is currently used as an adjunct with levodopa [101]. Recent data show that the A2A receptor counteract the aggregation, neuronal degeneration and toxicity induced by α-synuclein [112, 113].
P2X7	Thought to be expressed in neurons and glia, but their presence in neurons has recently been questioned [127, 128].	Glutamate release, stimulation of neuroimmune response, enhanced production of ROS, protein misfolding, and diminished BDNF levels, resulting in neuroplasticity impairment and/or neuronal damage [131, 146, 147].	HD: P2X7 receptor antagonism ameliorates motor coordination deficits and body weight loss, and inhibits neuronal loss in animal models of HD (Tet/HD94 and R6/1) [148]
			PD: P2X7 receptor blockade before 6-OHDA lesions in rats prevents depletion of dopamine in striatum [149], hinders the loss of tyrosine-hydroxylase immunoreactivity, attenuates rotational behavior and diminishes memory deficits [150]. P2X7 receptor antagonism re-establishes the dopaminergic nigrostriatal pathway, decreases rotation behavior and reduces microglial activation in 6-OHDA lesioned rats [151, 152]. Pretreatment of BV2 microglia [153] and neuroblastoma SH-SY5Y [154] cells with P2X7 receptor antagonists decreases ROS production and prevents abnormal calcium influx induced by α-synuclein, respectively.
A1	Neurons [170], microglia [171], astrocytes [171], oligodendrocytes [172].	Inhibits excitatory neurotransmitter release [170] and microglial activation [171], decreases astrocyte proliferation [171], stimulates oligodendrocyte migration [172].	A1 receptor activation protects against degeneration and decreases excitatory neurotransmission [158, 160].
P2X1	Sympathetic and sensory neurons, astrocytes, and oligodendrocytes [173].	Noradrenaline and acetylcholine co-transmitters [173].	PD: P2X1 receptor activation induces lysosomal dysfunction and increases α-synuclein aggregation [161].
P2Y6	mESC-derived GABAergic neurons [174] and activated microglia [175].	Induces microglial cytokine release and phagocytic activity [164] and microglial phagoptosis [166].	PD: P2Y6 receptor activation contributes to neurodegeneration possibly through microglial activation [152].

BDNF, brain-derived neurotrophic factor; HD, Huntington’s Disease; mESC, mouse embryonic stem cells; PD, Parkinson’s Disease; ROS, reactive oxygen species.