Research Priorities on the Role of α-Synuclein in Parkinson's Disease Pathogenesis.

Various forms of Parkinson's disease, including its common sporadic form, are characterized by prominent α-synuclein (αSyn) aggregation in affected brain regions. However, the role of αSyn in the pathogenesis and evolution of the disease remains unclear, despite vast research efforts of more than a quarter century. A better understanding of the role of αSyn, either primary or secondary, is critical for developing disease-modifying therapies. Previous attempts to hone this research have been challenged by experimental limitations, but recent technological advances may facilitate progress. The Scientific Issues Committee of the International Parkinson and Movement Disorder Society (MDS) charged a panel of experts in the field to discuss current scientific priorities and identify research strategies with potential for a breakthrough. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Rethinking the network determinants of motor disability in Parkinson's disease.

For roughly the last 30 years, the notion that striatal dopamine (DA) depletion was the critical determinant of network pathophysiology underlying the motor symptoms of Parkinson's disease (PD) has dominated the field. While the basal ganglia circuit model underpinning this hypothesis has been of great heuristic value, the hypothesis itself has never been directly tested. Moreover, studies in the last couple of decades have made it clear that the network model underlying this hypothesis fails to incorporate key features of the basal ganglia, including the fact that DA acts throughout the basal ganglia, not just in the striatum. Underscoring this point, recent work using a progressive mouse model of PD has shown that striatal DA depletion alone is not sufficient to induce parkinsonism and that restoration of extra-striatal DA signaling attenuates parkinsonian motor deficits once they appear. Given the broad array of discoveries in the field, it is time for a new model of the network determinants of motor disability in PD.

Physiological involvement of presynaptic L-type voltage-dependent calcium channels in GABA release of cerebellar molecular layer interneurons.

While high threshold voltage-dependent Ca2+ channels (VDCCs) of the N and P/Q families are crucial for evoked neurotransmitter release in the mammalian CNS, it remains unclear to what extent L-type Ca2+ channels (LTCCs), which have been mainly considered as acting at postsynaptic sites, participate in the control of transmitter release. Here, we investigate the possible role of LTCCs in regulating GABA release by cerebellar molecular layer interneurons (MLIs) from rats. We found that BayK8644 (BayK) markedly increases mIPSC frequency in MLIs and Purkinje cells (PCs), suggesting that LTCCs are expressed presynaptically. Furthermore, we observed (1) a potentiation of evoked IPSCs in the presence of BayK, (2) an inhibition of evoked IPSCs in the presence of the LTCC-specific inhibitor Compound 8 (Cp8), and (3) a strong reduction of mIPSC frequency by Cp8. BayK effects are reduced by dantrolene, suggesting that ryanodine receptors act in synergy with LTCCs. Finally, BayK enhances presynaptic AP-evoked Ca2+ transients and increases the frequency of spontaneous axonal Ca2+ transients observed in TTX. Taken together, our data demonstrate that LTCCs are of primary importance in regulating GABA release by MLIs.

Cholinergic modulation of striatal nitric oxide-producing interneurons.

Striatal GABAergic interneurons that express nitric oxide synthase-so-called low-threshold spike interneurons (LTSIs)-play several key roles in the striatum. But what drives the activity of these interneurons is less well defined. To fill this gap, a combination of monosynaptic rabies virus mapping (msRVm), electrophysiological and optogenetic approaches were used in transgenic mice in which LTSIs expressed either Cre recombinase or a fluorescent reporter. The rabies virus studies revealed a striking similarity in the afferent connectomes of LTSIs and neighboring cholinergic interneurons, particularly regarding connections arising from the parafascicular nucleus of the thalamus and cingulate cortex. While optogenetic stimulation of cingulate inputs excited both cholinergic interneurons and LTSIs, thalamic stimulation excited cholinergic interneurons, but inhibited LTSIs. This inhibition was dependent on cholinergic interneurons and had two components: a previously described GABAergic element and one that was mediated by M4 muscarinic acetylcholine receptors. In addition to this phasic signal, cholinergic interneurons tonically excited LTSIs through a distinct, M1 muscarinic acetylcholine receptor pathway. This coordinated cholinergic modulation of LTSIs predisposed them to rhythmically burst in response to phasic thalamic activity, potentially reconfiguring striatal circuitry in response to salient environmental stimuli.

Determinants of dopaminergic neuron loss in Parkinson's disease.

The cardinal motor symptoms of Parkinson's disease (PD) are caused by the death of dopaminergic neurons in the substantia nigra pars compacta (SNc). Alpha-synuclein (aSYN) pathology and mitochondrial dysfunction have been implicated in PD pathogenesis, but until recently it was unclear why SNc dopaminergic neurons should be particularly vulnerable to these two types of insult. In this brief review, the evidence that SNc dopaminergic neurons have an anatomical, physiological, and biochemical phenotype that predisposes them to mitochondrial dysfunction and synuclein pathology is summarized. The recognition that certain traits may predispose neurons to PD-linked pathology creates translational opportunities for slowing or stopping disease progression.

Striatal cholinergic interneurons and Parkinson's disease.

Giant, aspiny cholinergic interneurons (ChIs) have long been known to be key nodes in the striatal circuitry controlling goal-directed actions and habits. In recent years, new experimental approaches, like optogenetics and monosynaptic rabies virus mapping, have expanded our understanding of how ChIs contribute to the striatal activity underlying action selection and the interplay of dopaminergic and cholinergic signaling. These approaches also have begun to reveal how ChI function is distorted in disease states affecting the basal ganglia, like Parkinson's disease (PD). This review gives a brief overview of our current understanding of the functional role played by ChIs in striatal physiology and how this changes in PD. The translational implications of these discoveries, as well as the gaps that remain to be bridged, are discussed as well.

The origins of oxidant stress in Parkinson's disease and therapeutic strategies.

Parkinson's disease (PD) is a major world-wide health problem afflicting millions of the aged population. Factors that act on most or all cell types (pan-cellular factors), particularly genetic mutations and environmental toxins, have dominated public discussions of disease etiology. Although there is compelling evidence supporting an association between disease risk and these factors, the pattern of neuronal pathology and cell loss is difficult to explain without cell-specific factors. This article focuses on recent studies showing that the neurons at greatest risk in PD-substantia nigra pars compacta dopamine neurons-have a distinctive physiological phenotype that could contribute to their vulnerability. The opening of L-type calcium channels during autonomous pacemaking results in sustained calcium entry into the cytoplasm of substantia nigra pars compacta dopamine neurons, resulting in elevated mitochondrial oxidant stress and susceptibility to toxins used to create animal models of PD. This cell-specific stress could increase the negative consequences of pan-cellular factors that broadly challenge either mitochondrial or proteostatic competence. The availability of well-tolerated, orally deliverable antagonists for L-type calcium channels points to a novel neuroprotective strategy that could complement current attempts to boost mitochondrial function in the early stages of the disease.