Topography of FUS pathology distinguishes late-onset BIBD from aFTLD-U

Abstract

BackgroundMultiple neurodegenerative diseases are characterized by the abnormal accumulation of FUS protein including various subtypes of frontotemporal lobar degeneration with FUS inclusions (FTLD-FUS). These subtypes include atypical frontotemporal lobar degeneration with ubiquitin-positive inclusions (aFTLD-U), basophilic inclusion body disease (BIBD) and neuronal intermediate filament inclusion disease (NIFID). Despite considerable overlap, certain pathologic features including differences in inclusion morphology, the subcellular localization of inclusions, and the relative paucity of subcortical FUS pathology in aFTLD-U indicate that these three entities represent related but distinct diseases. In this study, we report the clinical and pathologic features of three cases of aFTLD-U and two cases of late-onset BIBD with an emphasis on the anatomic distribution of FUS inclusions.ResultsThe aFTLD-U cases demonstrated FUS inclusions in cerebral cortex, subcortical grey matter and brainstem with a predilection for anterior forebrain and rostral brainstem. In contrast, the distribution of FUS pathology in late-onset BIBD cases demonstrated a predilection for pyramidal and extrapyramidal motor regions with relative sparing of cerebral cortex and limbic regions.ConclusionsThe topography of FUS pathology in these cases demonstrate the diversity of sporadic FUS inclusion body diseases and raises the possibility that late-onset motor neuron disease with BIBD neuropathology may exhibit unique clinical and pathologic features.

Poly-A Binding Protein-1 Localization to a Subset of TDP-43 Inclusions in Amyotrophic Lateral Sclerosis Occurs More Frequently in Patients Harboring an Expansion inC9orf72

“…FUS is an RNA binding protein that like TDP-43 forms NCIs in a number of neurodegenerative diseases (3-11). One such disease in which FUS forms NCIs in spinal cord motor neurons is BIBD, a progressive neurodegenerative disease with variable clinical phenotypes ranging from ALS to FTD (3, 11).…”

“…One such disease in which FUS forms NCIs in spinal cord motor neurons is BIBD, a progressive neurodegenerative disease with variable clinical phenotypes ranging from ALS to FTD (3, 11). Similar to TDP-43, FUS localizes to stress granules (27, 45).…”

“…A common pathological feature of almost all cases of ALS is the formation of neuronal cytoplasmic inclusions (NCIs) and dystrophic neurites containing the normally nuclear TAR-DNA binding protein of 43 kDa (TDP-43) (2). A second RNA binding protein that forms intraneuronal inclusions and is causative for a subset of ALS is the fused in sarcoma (FUS) protein (3-11). Detailed analysis of the proteins that help form and maintain pathological inclusions aids the understanding of the underlying cellular mechanisms that lead to degeneration of the motor neurons.…”

Activity-dependent FUS dysregulation disrupts synaptic homeostasis

“…S7 E and F). Upper or lower limb weakness is common in both ALS and FTLD with motor function deficits (32)(33)(34)(35). Changes in social interactions also are a common clinical feature of patients with FTLD and in ALS patients with dementia (1).…”

Imaging Translocator Protein as a Biomarker of Neuroinflammation in Dementia

“…Both familial and sporadic forms of FTLD often—though not always—result from the aggregation of abnormal tau filaments (Caroppo et al, 2016; Ferrer et al, 2014; He et al, 2016; Laws et al, 2008; Lee et al, 2013; Lindquist, Schwartz, Batbayli, Waldemar, & Nielsen, 2009). Other disorders considered under the larger umbrella of FTLD include the “Parkinson’s plus” disorders such as primary progressive palsy and corticobasal ganglionic degeneration; these are characterized by shared nigrostriatal cell loss and are pathologically defined by tau aggregation (Ioannidis, Konstantinopoulou, Maiovis, & Karacostas, 2012).…”