[11] According

to this classification by Mackenzie and colleagues, Type B refers MEK inhibitor to OPTN-ALS. As OPTN plays an important role in the maintenance of the GA,[12] loss of OPTN would conceivably induce fragmentation of the GA. This notion is supported by the fact that in the case with a homozygous OPTN null mutation presented here, virtually all the AHCs showed GA fragmentation. The GA is an important cellular organelle involved in the handling of proteins, and its dysfunction has been implicated in neurodegeneration.[13-15] Neuronal GA fragmentation is considered an early and probably irreversible change in the process of neurodegeneration that triggers apoptosis.[14] The fact that the GA is not damaged in non-motor cells suggests that the mechanisms that normally maintain the GA are different in these cells compared with motor neurons. OPTN co-localizes with TDP-43[1, 16] and fused in sarcoma (FUS)[17] in ALS inclusions. However, neuropathological findings in Patient 1 indicate that TDP-43 can form inclusions in the absence of OPTN. Similarly, OPTN-negative,

TDP-43-positive inclusions and frequent GA fragmentation within motor neurons were prominent pathological BI 2536 nmr features of patients heterozygous for the E478G OPTN mutation. OPTN null mutation in Patient 1 resulted in nonsense-mediated mRNA decay as indicated by the absence Megestrol Acetate of immunoreactivity for OPTN throughout the CNS. These results indicate that OPTN is not essential for the formation of TDP-43 inclusions and that OPTN loss-of-function may result in TDP-43 accumulation and GA fragmentation. Patient 1 was previously diagnosed with glaucoma. OPTN mutation is responsible for primary open-angle glaucoma (POAG) with autosomal dominant inheritance.[18] Histologically, Patient 1 showed mild optic-nerve cupping with no obvious trabecular meshwork changes, which is distinct from the typical pathological characteristics of POAG.[19] Furthermore, neither her parents nor Patient 2 and her parents had glaucoma, strongly suggesting that her glaucoma

was coincidental. In conclusion, we have provided the first description of ALS associated with an autosomal recessive (Q398X) OPTN mutation and TDP-43 pathology. The TDP-43 pathology of Q398X was similar to that of an autosomal dominant E478G mutation. Neuropathological examinations indicate that OPTN is not essential to the formation of TDP-43 inclusions and that OPTN loss-of-function, but not the proteinopathy itself, may result in TDP-43 accumulation and GA fragmentation. This work was supported in part by Grants-in-Aid from the Research Committee of CNS Degenerative Diseases, the Ministry of Health, Labour and Welfare of Japan, from the Japan Society for the Promotion of Science (No. 21500336 and no.