Subthalamic nucleus deep brain stimulation is neuroprotective in the A53T α‐synuclein Parkinson's disease rat model

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Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is considered a standard therapy for Parkinson's disease (PD),1 the second‐most common neurodegenerative disease, for which no cure is yet available. DBS has provided robust and long‐lasting improvement of levodopa‐sensitive motor symptoms, fluctuations, dyskinesia, and quality of life in several clinical trials.2 Much of this benefit emerges rapidly with a “make and break” mechanism related to high‐frequency stimulation and likely represents symptomatic benefit attributed to correction of abnormal network activity. With the application of DBS earlier in the course of disease, a putative disease‐modifying effect has become of clinical interest.5 Several potential mechanisms have been proposed by which DBS could act neuroprotective: STN‐DBS could reduce overactivity and excitotoxicity of glutamatergic projections from the STN to substantia nigra (SN).7 Moreover, DBS may induce the expression of brain‐derived neurotrophic factor (BDNF), a neurotrophic factor that is anterogradely transported from its site of synthesis and is known to support survival of dopaminergic neurons.9 Finally, improved motor activity as an indirect effect of symptomatic improvement could enhance neuronal survival.10
To date, there is no clinical evidence for STN‐DBS‐related disease modification, but this lack of evidence could simply reflect inappropriate trial methodologies.11 In contrast, numerous preclinical studies, conducted in rodent and nonhuman primate (NHP) models of PD have demonstrated a beneficial effect of STN lesion or STN‐DBS on SN neuronal survival.8 However, the common drawback of these preclinical studies was the use of toxin‐mediated PD models, either by 1 methyl‐4 phenyl 1,2,3,6‐tetrahydropyridine (MPTP) in NHP14 or 6‐hydroxydopamine (6‐OHDA) in rodents.12 These toxin models cause acute nigral lesions and do not adequately reflect the molecular pathology of human PD, specifically they do not exhibit α‐synuclein (aSyn)‐positive aggregates, a hallmark of PD, and therefore have limited translational value for studying disease‐modifying therapies.
Thus, in order to evaluate the disease‐modifying potential of DBS in a context where SN neurons are accumulating and under duress from pathological aSyn, we utilized a rat model for PD that is based on a vector driven (adeno‐associated virus [AAV] 1/2) overexpression of mutated A53T α‐synuclein (A53T‐aSyn) in dopaminergic neurons of the SN that leads to progressive and reliable neurodegeneration and motor impairment.20 This model mimics the neurobiological hallmarks of PD much closer than toxin models and is thus more suitable for the investigation of DBS mechanisms of action.
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