Amyotrophic lateral sclerosis, frontotemporal lobar dementia, and p62; A functional convergence?

摘要

Amyotrophic lateral sclerosis (ALS) is a familial disease in 10% of cases and is sporadic in 90%; investigations prior to the early 1990s focused on the more prevalent sporadic disease. A paradigm shift in approaches to disease pathogenesis began almost 2 decades ago, with the publication of 2 articles that documented the presence of mutations in Cu/Zn su-peroxide dismutase-1 in 20% of familial cases. These seminal studies refocused investigative efforts to patients with familial ALS, unleashing the power of genetics to illuminate the many different ways neurons succumb to the degenerative process. Discoveries of novel genetic mutations have also provided cogent evidence that ALS is linked to frontotemporal lobar dementia (FTLD), with reports of genes linked to rare cases of familial ALS and ALS-FTLD such as valosin-containing protein (VCP), TAR DNA binding protein TDP-43 (TARDBP), fused in sarcoma (FUS), optineurin (OPTN), and ubiquilin 2 (UBQLN2). Overall, many different mutations have been linked to ALS, to FTLD, or to both, supporting the etiologic diversity and clinical, pathologic, and genetic heterogeneity of these disorders. Recently, 2 study reports noted that the most common cause of familial ALS and FTLD is an expanded hexanucle-otide repeat of GGGGCC in a noncoding region of the C9Orf72, accounting for almost 40% to 50% of familial ALS and 4% to 6% of sporadic ALS, providing further support for the linkage between ALS and FTLD.