Polyglutamine-containing aggregates in neuronal intranuclear inclusion disease

The trinucleotide repeat disorders are a heterogeneous group of neurological diseases characterised by a similar genetic mutation. Eight disorders have been previously identified with expansion of a CAG repeat in the protein coding sequence of the disease gene, resulting in pathological expansion of a glutamine tract in the mutated protein. The presence of this common mutation suggests that a similar mechanism may underlie neurodegeneration. Studies 1 Lunkes A Mandel J-L Folyglutamines, nuclear inclusions and neurodegeneration. Nat Med. 1997; 3: 1201-1202 Crossref PubMed Scopus (53) Google Scholar have shown that mutated protein accumulates in the nuclei of neurons from patients with Machado-Joseph disease, Huntington's disease, and spinocerebellar ataxia type 1, and in transgenic mice expressing mutated ataxin-1 or an amino-terminal fragment of mutated huntingtin. These ubiquitinated intranuclear inclusions contain fibrillar aggregates which form amyloid-like structures in model systems. Large intranuclear aggregates have been observed in neurons and glia in another rare multisystem neurodegenerative disease known as neuronal intranuclear inclusion disease (NIID). 2 Haltia M Somer H Palo J Johnson WG Neuronal intranuclear inclusion disease in identical twins. Ann Neurol. 1984; 15: 316-321 Crossref PubMed Scopus (70) Google Scholar , 3 Munoz-Garcia D Ludwin SK Adult-onset neuronal intranuclear hyaline inclusion disease. Neurology. 1986; 36: 785-790 Crossref PubMed Google Scholar , 4 Schuffler MD Bird TD Sumi SM Cook A A familial neuronal disease presenting as intestinal pseudoobstrution. Gastroenterology. 1978; 75: 889-898 PubMed Scopus (169) Google Scholar This disorder usually affects the young with death by the third decade. Both sporadic and familial cases have been described, and the mode of inheritance is unclear. Patients often present with extrapyramidal signs, lower motor neuron abnormalities, and cognitive or behavioural dysfunction. Neurons of the central, peripheral, and autonomic nervous systems show eosinophilic, ubiquitinated intranuclear inclusions. The similarities between this disease and the CAG repeat disorders prompted us to examine whether expanded polyglutamine tracts could be identified in NIID.