DRPLA is characterized by marked, generalized brain atrophy and the accumulation of atrophin-1 with expanded glutamine stretches. Mutant atrophin-1 proteins have been found in neuronal intranuclear inclusions (NII) and diffusely accumulated in the neuronal nuclei. While the role of NIIs (pathologic or protective) is unclear, the diffuse accumulation of mutant protein is regarded as toxic. Brain atrophy There is significant reduction in CNS tissue throughout the brain and spinal cord, with brain weights of DRPLA patients often becoming less than 1000g. In regions lacking obvious neuronal depletion, atrophy of the neuropil is noted. The globus pallidus (lateral greater than medial segment) and subthalamic nucleus demonstrate consistent neuronal loss and astrocytic gliosis. The dentate nucleus shows neuronal loss with the remaining atrophic neurons exhibiting grumose degeneration. In general, the<unk>  degeneration is more severe than the<unk>  degeneration in juvenile-onset and the reverse is true for the late adult-onset. Transgenic DRPLA mice demonstrated several neuronal abnormalities including a reduction in the number and size of dendritic spines as well as in the area of perikarya and diameter of dendrites. Spine morphology and density have been linked to learning and memory functions as well as epilepsy. The stubby-type spines seen in DRPLA mice are morphologically different from the thin and mushroom-type spines seen in Huntington’s mice. Morphometric analysis of DRPLA mouse brains has shown a loss of normal inter-microtubule spacing in neuronal axons. The microtubules were relatively compacted, suggesting abnormalities in protein transport may play a role in neuronal degeneration. In humans, atrophin-1 interacts with IRSp53, which interacts with Rho GTPases to regulate the organization of the actin cytoskeleton and the pathways that regulate lamellipodia and filopodia. Neuronal intranuclear inclusions NIIs are not exclusive to DRPLA; they have been found in a variety of neurodegenerative disorders. In DRPLA, NIIs have been demonstrated in both neurons and glial cells in the striatum, pontine nuclei, inferior olive, cerebellar cortex and dentate nucleus, though the incidence of neurons with NIIs is low, roughly 1-3%. In DRPLA, the NIIs are spherical, eosinophilic structures of various sizes. They are non-membrane-bound and are composed of both granular and filamentous structures. They are ubiquitinated and may be paired or in doublet form within the nucleus. NIIs are immunopositive for several transcription factors such as TATA binding protein (TBP), TBP-associated factor (TAFII130), Sp1, camp-responsive element-binding protein (CREB) and CREB-binding protein (CBP). It has been proposed that recruitment of transcription factors into NIIs may induce transcriptional abnormalities that contribute to progressive neuronal degeneration. Other polyQ disorders, such as Huntington’s and spinocerebellar ataxia (types 3 and 7), have been demonstrated to sequester some of the same transcriptions factors. That different gene products sequester the same transcription factors may contribute to the overlapping symptoms of genetically different diseases. NIIs have also been demonstrated to alter the distribution of the intranuclear structures, such as promyelocytic leukemia protein (PML) nuclear bodies. Although the role of PML bodies is unclear, they are believed to be involved in apoptosis. In neurons with NII, PML bodies in DRPLA patients form a shell or ring around the ubiquitinated core. In similar polyQ diseases, the association of this PML shell has been shown to be size-dependent with larger NIIs being PML negative. This has led to two models, one in which PML bodies represent sites for NII formation and a second in which PML bodies are involved in degradation and proteolysis of NIIs. Filementous, atrophin-1 positive, inclusions are also observed exclusively in the cytoplasm of the dentate nucleus, which are extremely similar to the inclusions observed in the motor neurons in amyotrophic lateral sclerosis. Diffuse accumulation in the nuclei In DRPLA, diffuse accumulation of mutant ATN1 occurs far more extensively than NII formation. The extent and frequency of neurons showing the diffuse nuclear accumulations changes depending on CAG repeat length. It is believed that the diffuse nuclear accumulations contribute to the clinical features such as dementia and epilepsy. ATN1 contains both a nuclear localization sequence and a nuclear export sequence. Cleavage of ATN1 to an N terminal fragment relieves ATN1 of its nuclear export signal and concentrates it in the nucleus. Increased nuclear concentrations have been demonstrated via transfection assay to enhance cellular toxicity. In both the juvenile and adult forms, regions in which more than 40% of neurons became immunoreactive to 1C2 (a monoclonal antibody against expanded polyglutamine stretches) included: the nucleus basalis of Meynert, large striatal neurons, globus pallidus, subthalamic nucleus, thalamic intralaminar nucleus, lateral geniculate body, oculomotor nucleus, red nucleus, substantia nigra, trigeminal motor nucleus, nucleus raphes pontis, pontine nuclei, vestibular nucleus, inferior olive and the cerebellar dentate nucleus. The juvenile type also shows reactivity in the cerebral cortex, hippocampal CA1 area, and the reticular formation of the brainstem. Nuclei containing accumulations of mutant atrophin-1 are deformed with nuclear membrane indentations.
Dentatorubral–pallidoluysian atrophy
Cerebellar abiotrophy
Central chromatolysis
Corticobasal degeneration
Olivopontocerebellar atrophy
Spinal muscular atrophy with lower extremity predominance 1
Cerebellar degeneration
Multi/minicore myopathy