Ubiquitin-immunoreactive intraneuronal inclusions in amyotrophic lateral sclerosis. Morphology, distribution, and specificity.

Antibodies to ubiquitin have been used to search for evidence of abnormal protein degradation in amyotrophic lateral sclerosis--motor neuron disease (ALS). Anterior horn cell ubiquitin-immunoreactive (IR) inclusions were present in all of 31 ALS cases but in none of 23 neurologically normal and in only 1 of 22 neurologically abnormal controls. These inclusions, which were present in familial and sporadic ALS cases, and in cases with dementia, took the form of dense rounded or irregular ubiquitin-IR cytoplasmic inclusions (dense bodies), or loosely arranged bundles ('skeins') of filamentous-appearing material. The presence of ubiquitin-IR inclusions corresponded to the pattern of selective neuronal vulnerability in ALS, although inclusions in pyramidal neurons of the motor cortex were infrequent and were noted in only a minority of cases. Ubiquitin-IR inclusions were more prevalent than Bunina bodies. The latter were present in 67% of ALS cases but were seldom labelled by antibodies to ubiquitin. Intraneuronal inclusions resembling Lewy bodies were present in 23% of ALS cases and were often identified by antibodies to ubiquitin. We conclude that the presence of ubiquitin-IR inclusions in lower motor neurons represents a characteristic pathological feature of ALS in its various clinical forms. Ubiquitin-IR inclusions in ALS differ from ubiquitinated inclusions in other neuronal degenerations in that they are not readily identified by antibodies to cytoskeletal proteins. They may represent accumulations of altered or abnormal neuronal proteins resistant to degradation via the ubiquitin proteolytic pathway.