Neuronal intranuclear inclusion disease (NIID) has highly variable clinical manifestations. Sone et al. describe the clinical and pathological features of 57 adult-onset cases diagnosed by postmortem dissection/antemortem skin biopsy. They report ‘dementia dominant’ and ‘limb weakness’ subtypes, and recommend consideration of NIID in the differential diagnosis of leukoencephalopathy and neuropathy.

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Skin biopsy is an effective and less invasive antemortem diagnostic tool for NIID.

Mutations in the Cu/Zn-superoxide dismutase (SOD1) gene cause familial amyotrophic lateral sclerosis (ALS) through the gain of a toxic function; however, the nature of this toxic function remains largely unknown. Ubiquitylated aggregates of mutant SOD1 proteins in affected brain lesions are pathological hallmarks of the disease and are suggested to be involved in several proposed mechanisms of motor neuron death. Recent studies suggest that mutant SOD1 readily forms an incorrect disulfide bond upon mild oxidative stress in vitro, and the insoluble SOD1 aggregates in spinal cord of ALS model mice contain multimers cross-linked via intermolecular disulfide bonds. Here we show that a non-physiological intermolecular disulfide bond between cysteines at positions 6 and 111 of mutant SOD1 is important for high molecular weight aggregate formation, ubiquitylation, and neurotoxicity, all of which were dramatically reduced when the pertinent cysteines were replaced in mutant SOD1 expressed in Neuro-2a cells. Dorfin is a ubiquityl ligase that specifically binds familial ALS-linked mutant SOD1 and ubiquitylates it, thereby promoting its degradation. We found that Dorfin ubiquitylated mutant SOD1 by recognizing the Cys 6 -and Cys 111 -disulfide cross-linked form and targeted it for proteasomal degradation.Cu/Zn superoxide dismutase (SOD1), 2 a major intracellular antioxidant enzyme, metabolizes superoxide radicals to molecular oxygen and hydrogen peroxide (1, 2). Because mutations in SOD1 linked to familial amyotrophic lateral sclerosis (ALS) were first identified (3), more than 100 mutations at over 70 residues in the 153-amino acid SOD1 protein have been reported (4). Most mutations are missense mutations, with a few causing early termination or frame shifts near the carboxyl terminus of the protein. SOD1 mutations account for ϳ20% of familial ALS, which is characterized by selective degeneration of motor neurons. SOD1 is primarily a cytosolic protein (5), and the active enzyme is a homodimer of two subunits (6). Each subunit contains four cysteine (Cys) residues at positions 6, 57, 111, and 146. An intramolecular disulfide bond between Cys 57 and Cys 146 of each subunit facilitates its correct folding and stabilizes the active homodimeric structure (7, 8), but it is not known how the disulfide is formed in the reducing environment of the cytosol. Although the endoplasmic reticulum is the specialized site for oxidative folding (9), there is no SOD1 localization to the endoplasmic reticulum (10). Most familial ALS-linked mutations render SOD1 more susceptible to intramolecular disulfide bond reduction (11) and accelerate the rate of protein turnover (12, 13). Recent lines of evidence implicate the disulfide-reduced monomer as the common aggregation-prone, neurotoxic intermediate of mutant SOD1 proteins (8,11,[14][15][16], and a significant fraction of the insoluble SOD1 aggregates in the spinal cord of mutant SOD1 transgenic mice contains high molecular weight species cross-linked via intermolecular disulfide bonds (17). H...

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