Postsynaptic movement disorders: clinical phenotypes, genotypes, and disease mechanisms

Abstract

Movement disorders comprise a group of heterogeneous diseases with often complex clinical phenotypes. Overlapping symptoms and a lack of diagnostic biomarkers may hamper making a definitive diagnosis. Next-generation sequencing techniques have substantially contributed to unraveling genetic etiologies underlying movement disorders and thereby improved diagnoses. Defects in dopaminergic signaling in postsynaptic striatal medium spiny neurons are emerging as a pathogenic mechanism in a number of newly identified hyperkinetic movement disorders. Several of the causative genes encode components of the cAMP pathway, a critical postsynaptic signaling pathway in medium spiny neurons. Here, we review the clinical presentation, genetic findings, and disease mechanisms that characterize these genetic postsynaptic movement disorders.

Fig. 1

Basal ganglia motor circuits in normal physiology and hyperkinetic movement disorders. (a) Basal ganglia circuits in normal condition showing direct and indirect-pathway projections from dopaminergic neurons of the substantia nigra pars compacta to the subthalamic nucleus, the globus pallidus internal segment, and the substantia nigra pars reticulata. (b) Overactivation of the direct pathway in dystonia, and (c) hypofunction of the indirect pathway in chorea ultimately lead to disinhibition of thalamocortical neurons and hyperkinesia. SNc, substantia nigra pars compacta; Gpe, globus pallidus external segment; STN, subthalamic nucleus; Gpi, globus pallidus internal segment; SNr, substantia nigra pars reticulata; PPN, pedunculopontine nucleus (brainstem)

Fig. 2

Schematic overview on a striatal medium spiny neuron synapse. Dopaminergic signaling in striatal medium spiny neurons is mediated by the cAMP signaling pathway. Activation of D1-type dopamine receptors leads to activation of adenylyl cyclase 5 and subsequent increase in cAMP levels, while activation of D2-type dopamine receptors results in inhibition of adenylyl cyclase 5 and reduced levels of cAMP. cAMP in turn modulates activity of the protein kinase A, which phosphorylates further downstream effectors including DARP-32 and CREB. Arrows indicate mutations in genes involved in postsynaptic dopaminergic signaling in striatal medium spiny neurons