On the Right Track to Treat Movement Disorders: Promising Therapeutic Approaches for Parkinson's and Huntington's Disease

Abstract

Movement disorders are neurological conditions in which patients manifest a diverse range of movement impairments. Distinct structures within the basal ganglia of the brain, an area involved in movement regulation, are differentially affected for every disease. Among the most studied movement disorder conditions are Parkinson's (PD) and Huntington's disease (HD), in which the deregulation of the movement circuitry due to the loss of specific neuronal populations in basal ganglia is the underlying cause of motor symptoms. These symptoms are due to the loss principally of dopaminergic neurons of the substantia nigra (SN) par compacta and the GABAergic neurons of the striatum in PD and HD, respectively. Although these diseases were described in the 19th century, no effective treatment can slow down, reverse, or stop disease progression. Available pharmacological therapies have been focused on preventing or alleviating motor symptoms to improve the quality of life of patients, but these drugs are not able to mitigate the progressive neurodegeneration. Currently, considerable therapeutic advances have been achieved seeking a more efficacious and durable therapeutic effect. Here, we will focus on the new advances of several therapeutic approaches for PD and HD, starting with the available pharmacological treatments to alleviate the motor symptoms in both diseases. Then, we describe therapeutic strategies that aim to restore specific neuronal populations or their activity. Among the discussed strategies, the use of Neurotrophic factors (NTFs) and genetic approaches to prevent the neuronal loss in these diseases will be described. We will highlight strategies that have been evaluated in both Parkinson's and Huntington's patients, and also the ones with strong preclinical evidence. These current therapeutic techniques represent the most promising tools for the safe treatment of both diseases, specifically those aimed to avoid neuronal loss during disease progression.

Keywords: Huntington’s disease; Parkinson’s disease; cellular replacement; gene modifiers; neurotrophic factors; pharmacological therapy.

Figure 1

I Schematic representation of the direct and indirect pathways in basal ganglia in physiological, Parkinson’s (PD), and Huntington’s disease (HD) conditions. (A) Physiologically, the direct (green line) pathway participates in the activation of movement. This pathway is engaged when the activation of the cortex produces a release of glutamate into the striatum, activating GABAergic medium spiny neurons (MSNs) of the direct pathway. By releasing GABA to the substantia nigra pars reticulata (SNpr) and the internal globus pallidus (GPi), MSNs inhibit neurons of the SNpr/GPi that are also GABAergic. This causes activation of the glutamatergic neurons present in the thalamus, which projects to the cortex, resulting in the activation of movements. On the contrary, the indirect pathway (red line) participates in the inhibition of movement. When GABAergic MSNs that indirectly project to the SNpr through the external globus pallidus (GPe) and the subthalamic nucleus (STN), release GABA into the GPe, inhibits GABAergic neurons present in the GPe. This leads to the disinhibition of the glutamatergic neurons of the STN, which activates GABAergic neurons of the SNpr/GPi. These neurons inhibit neurons present in the thalamus, resulting in a reduction of movement. The selection and execution of movement reflect a dynamic balance between both pathways. (B) In PD, the loss of dopaminergic neurons of the SNpc, induces an overactivation of the indirect pathway and decrease of movement. Consequently, there is an increase of GABAergic activity of the GPi/SNpr over thalamic neurons that project to the cortex, leading to loss of movement (hypokinetic disorder). (C) In HD (early stage), MSNs of the indirect pathway appear to be affected before the MSNs of the direct pathway. This induces an increase of GABAergic (or inhibitor) activity of the GPe over the STN, which causes the loss of inhibitory activity of the GPi/SNpr over thalamic neurons that project to cortex, leading to the appearance of choreic movements (hyperkinetic disorder).

Figure 2

I Schematic representation of the different treatments for motor symptoms for PD and HD under clinical and preclinical phases. (A) Approaches regarding cellular, neurotrophic, electrical, and gene-modifying therapies that are in clinical trials or stage of optimization for PD and HD patients. The lines indicate the different brain structures that are the target of the therapeutic strategies mentioned. (B) Approaches regarding cellular, neurotrophic, electrical, and disease-modifying therapies in the preclinical phase using rodent models of PD and/or HD. The lines indicate the different brain structures that are the target of the therapeutic strategies mentioned.