No parkinsonism in SCA2 and SCA3 despite severe neurodegeneration of the dopaminergic substantia nigra

Abstract

See Klockgether (doi:10.1093/awv253) for a scientific commentary on this article. The spinocerebellar ataxias types 2 (SCA2) and 3 (SCA3) are autosomal dominantly inherited cerebellar ataxias which are caused by CAG trinucleotide repeat expansions in the coding regions of the disease-specific genes. Although previous post-mortem studies repeatedly revealed a consistent neurodegeneration of the dopaminergic substantia nigra in patients with SCA2 and with SCA3, parkinsonian motor features evolve only rarely. As the pathophysiological mechanism how SCA2 and SCA3 patients do not exhibit parkinsonism is still enigmatic, we performed a positron emission tomography and a post-mortem study of two independent cohorts of SCA2 and SCA3 patients with and without parkinsonian features. Positron emission tomography revealed a significant reduction of dopamine transporter levels in the striatum as well as largely unaffected postsynaptic striatal D2 receptors. In spite of this remarkable pathology in the motor mesostriatal pathway, only 4 of 19 SCA2 and SCA3 patients suffered from parkinsonism. The post-mortem investigation revealed, in addition to an extensive neuronal loss in the dopaminergic substantia nigra of all patients with spinocerebellar ataxia, a consistent affection of the thalamic ventral anterior and ventral lateral nuclei, the pallidum and the cholinergic pedunculopontine nucleus. With the exception of a single patient with SCA3 who suffered from parkinsonian motor features during his lifetime, the subthalamic nucleus underwent severe neuronal loss, which was clearly more severe in its motor territory than in its limbic or associative territories. Our observation that lesions of the motor territory of the subthalamic nucleus were consistently associated with the prevention of parkinsonism in our SCA2 and SCA3 patients matches the clinical experience that selective targeting of the motor territory of the subthalamic nucleus by focal lesions or deep brain stimulation can ameliorate parkinsonian motor features and is likely to counteract the manifestation of parkinsonism in SCA2 and SCA3 despite a severe neurodegeneration of the dopaminergic substantia nigra.