Spinocerebellar ataxia type 3 (SCA-3)/Machado-Joseph disease (MJD), the most common autosomal dominant ataxia, affects many regions of the brain and spinal cord. Similar to SCA-1, SCA-2, SCA-6, SCA-7, and SCA-17, the mutation consists of a pathogenic translated cytosine-adenine-guanine (CAG) trinucleotide repeat expansion. Almost invariably, the substantia nigra and the dentate nucleus of the cerebellum bear the brunt of the disease, and these lesions account for the Parkinsonian and ataxic phenotypes. Lesions of motor nuclei in the brain stem cause the complex disturbance of ocular motility and weakness of the tongue. Atrophy of the basis pontis is common, and polyglutamine-positive neuronal intranuclear inclusion bodies are most readily found in the pontine gray. Abnormalities of basal ganglia, thalamus, spinal cord, dorsal root ganglia, and sensory peripheral nerves are more variable. This report of the main neuropathological lesions is based on the study of 12 genetically confirmed autopsy cases of SCA-3/MJD. In the cerebellum, all layers of the cortex remain normal, but the dentate nucleus exhibits neuronal loss and a peculiar proliferation of synaptic terminals termed grumose regeneration. The clusters surrounding residual neuronal cell bodies and dendrites are interpreted as a response to loss of γ-aminobutyric acid (GABA)-A-receptors and lack of gephyrin, a protein that accomplishes the proper positioning of GABA-A- and glycine receptors. At the spinal level, dorsal root ganglia reveal proliferation of satellite cells, active neuronal destruction, and residual nodules. The spinal cord shows total or subtotal loss of neurons in the dorsal nuclei, anterior horn cell atrophy, and variable long tract degeneration. While misfolding of ataxin-3 due to overly long polyglutamine stretches is a critical contributor to the pathogenesis of SCA-3/MJD, the great neuropathological complexity of the disorder remains largely unexplained.
Spinocerebellar ataxia type 3 Machado-Joseph disease Dentate nucleus Substantia nigra Inclusion bodies
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The author gratefully acknowledges the families who generously allowed the harvesting of autopsy tissues for research in SCA-3/MJD. The procurement of autopsy specimens was made possible by financial support from the National Ataxia Foundation, Minneapolis, MN, USA. The work was completed in the research laboratories of the Veterans Affairs Medical Center in Albany, NY, USA. Ms. Alyssa B. Becker provided expert technical assistance.
Woods BT, Schaumburg HH (1972) Nigro-spino-dentatal degeneration with nuclear ophthalmoplegia. A unique and partially treatable clinico-pathological entity. J Neurol Sci 17:149–166CrossRefGoogle Scholar
Nakano KK, Dawson DM, Spence A (1972) Machado disease: a hereditary ataxia in Portuguese emigrants to Massachusetts. Neurology 22:49–55CrossRefGoogle Scholar
Coutinho P, Guimarães A, Scaravilli F (1982) The pathology of Machado-Joseph disease. Acta Neuropathol 58:48–54CrossRefGoogle Scholar
Rosenberg RN, Nyhan WL, Bay C, Shore P (1976) Autosomal dominant striatonigral degeneration. A clinical, pathologic, and biochemical study of a new genetic disorder. Neurology 26:703–714CrossRefGoogle Scholar
Kawaguchi Y, Okamoto T, Taniwaki M, Aizawa M, Inoue M, Katayama S, Kawakami H, Nakamura S, Nishimura M, Akiguchi I, Kimura J, Narumiya S, Kakizuka A (1994) CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1. Nat Genet 8:221–228CrossRefGoogle Scholar
Riess O, Rüb U, Pastore A, Bauer P, Schöls L (2008) SCA3: neurological features, pathogenesis and animal models. Cerebellum 7:125–137CrossRefGoogle Scholar
Romanul FCA, Fowler HL, Radvany J, Feldman RG, Feingold M (1977) Azorean disease of the nervous system. New Engl J Med 296:1505–1508CrossRefGoogle Scholar
Becker PE, Sabuncu N, Hopf HC (1971) Dominant erblicher Typ von “cerebellarer Ataxie”. Z Neurol 199:116–139PubMedGoogle Scholar
Coutinho P, Guimarães A, Pires MM, Scaravilli F (1986) The peripheral neuropathy in Machado-Joseph disease. Acta Neuropathol 71:119–124CrossRefGoogle Scholar
Colomer Gould VF (2012) Mouse models of spinocerebellar ataxia type 3 (Machado-Joseph disease). Neurotherapeutics 9:285–296CrossRefGoogle Scholar
Bettencourt C, Lima M (2011) Machado-Joseph disease: from first descriptions to new perspectives. Orphanet J Rare Dis 6:35CrossRefGoogle Scholar
Matilla-Dueñas A (2012) Machado-Joseph disease and other rare spinocerebellar ataxias. Adv Exp Med Biol 724:172–188CrossRefGoogle Scholar
Paulson HL (2007) Dominantly inherited ataxias: lessons learned from Machado-Joseph disease/spinocerebellar ataxia type 3. Semin Neurol 27:133–142CrossRefGoogle Scholar
Rüb U, Brunt ER, Deller T (2008) New insights into the pathoanatomy of spinocerebellar ataxia type 3 (Machado-Joseph disease). Curr Opin Neurol 21:111–116CrossRefGoogle Scholar
Koeppen AH, Ramirez RL, Becker AB, Feustel PJ, Mazurkiewicz JE (2015) Friedreich ataxia: failure of GABA-ergic and glycinergic synaptic transmission in the dentate nucleus. J Neuropathol Exp Neurol 74:166–176CrossRefGoogle Scholar
Prior P, Schmitt B, Grenningloh G, Pribilla I, Multhaup G, Beyreuther K, Maulet Y, Werner P, Langosh D, Kirsch J, Betz H (1992) Primary structure and alternative splice variants of gephyrin, a putative glycine-receptor-tubulin linker protein. Neuron 8:1161–1170CrossRefGoogle Scholar
Koeppen AH, Davis AN, Morral JA (2011) The cerebellar component of Friedreich’s ataxia. Acta Neuropathol 122:323–330CrossRefGoogle Scholar