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.
Highlights
Movement disorders are characterized by disabilities in speed, fluency, quality, and ease of motor execution, impairments that could be due to an excess or lack of voluntary movements (Shipton, 2012)
The basal ganglia structure comprises a group of subcortical nuclei including the striatum, internal globus pallidus (GPi) and external globus pallidus (GPe), substantia nigra (SN) pars reticulata (SNpr) and compacta (SNpc), and subthalamic nucleus (STN), that together with the primary motor cortex and the thalamus, comprise the motor circuit involved in the control of voluntary movement (Albin et al, 1989; Obeso et al, 2008; Calabresi et al, 2014)
PD and Huntington’s disease (HD) are movement disorders characterized by the presence of aberrant and unwanted involuntary movements
Summary
Movement disorders are characterized by disabilities in speed, fluency, quality, and ease of motor execution, impairments that could be due to an excess or lack of voluntary movements (Shipton, 2012). These studies set foot for the first PD cell replacement therapy in humans These clinical trials were performed using dopaminergic neuron precursors from human fetal tissue, which were transplanted into the striatum of PD patients (Lindvall et al, 1989, 1992; Freed et al, 1990, 1992). Using both approaches, Hallett et al (2015) demonstrated that in a non-human primate PD model autologous iPSCs-derived midbrain-like dopaminergic neurons could successfully engraft and survive for as long as 2 years This led to improving motor function and complete re-innervation in the striatum with extensive axonal outgrowth, and no graft overgrowth, tumor formation or inflammation was observed (Hallett et al, 2015). It is important to remember that dopaminergic neuron replacement is primarily
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