Multiple Proteinopathies in Familial ALS Cases With Optineurin Mutations

Optineurin (OPTN) is a causative gene in familial amyotrophic lateral sclerosis (ALS) with transactivation response element DNA-binding protein of 43 kDa (TDP-43) protein pathology. Here, we report multiple proteinopathies in familial ALS cases with OPTN mutations. We examined the TDP-43, tau, and α-synuclein pathology of ALS cases with OPTN mutations including 2 previously reported cases (Cases 1 and 2) and 1 newly autopsied case (Case 3) that was clinically diagnosed as ALS and Parkinson disease with a heterozygous E478G OPTN mutation. Pathologic examination of Case 3 showed motor neuron degeneration and depigmentation of the substantia nigra. Neurofibrillary tangles (NFTs) were seen in the hippocampus, pontine tegmentum, and spinal cord. Accumulation of multiple proteins including phosphorylated TDP-43-positive neuronal cytoplasmic inclusions, phosphorylated tau (AT8)-positive NFTs, and α-synuclein-positive Lewy bodies were observed in the substantia nigra. The other 2 cases had a similar distribution of tau pathology, but lacked synuclein pathology. Consecutive sections of Case 3 revealed pTDP-43, AT8, and α-synuclein-positive inclusions in the same neuron and double immunofluorescence staining showed aggregation of different proteins (tau and α-synuclein, or tau and TDP-43) in the same neuron. Our results support the notion that OPTN mutations may lead to multiple proteins aggregation and neuronal degeneration.