MAPT and Parkinson disease: For example, tau in frontotemporal lobar dementia with Ub-positive inclusions and α-synuclein in PD bind LAMP-2A with an unusually high affinity, leading to a traffic jam during cargo translocation across the lysosomal membrane.89 Yet another risk factor underlying dysregulation of autophagy in aged neurons is a genetic mutation in a regulator of autophagy, such as p62, whose mutations are implicated in the pathogenesis of familial and sporadic ALS32, characterized by p62-positive inclusions in affected neurons.90