Extensive FUS‐Immunoreactive Pathology in Juvenile Amyotrophic Lateral Sclerosis with Basophilic Inclusions

Abstract

Juvenile amyotrophic lateral sclerosis (ALS) with basophilic inclusions is a well-recognized entity. However, the molecular underpinnings of this devastating disease are poorly understood. Here, we present genetic and neuropathological characterizations in two young women with fatal rapidly progressive ALS with basophilic inclusions. In one case, a germline mutation (P525L) was detected in the FUS/TLS (fused in sarcoma/translocated in liposarcoma) gene, whereas no mutation was identified in the other case. Postmortem examination in both cases revealed severe loss of spinal motor neurons with remaining neurons showing basophilic inclusions that contain abnormal aggregates of FUS proteins and disorganized intracellular organelles, including mitochondria and endoplasmic reticulum. In both patients, the FUS-positive inclusions were also detected in neurons in layers IV-V of cerebral cortex and several brainstem nuclei. In contrast, spinal motor neurons in patients with late-onset sporadic ALS showed no evidence of abnormal accumulation of FUS protein. These results underscore the importance of FUS mutations and pathology in rapidly progressive juvenile ALS. Furthermore, our study represents the first detailed characterizations of neuropathological findings in rapidly progressive juvenile ALS patients with a mutation in the FUS/TLS gene.

Juvenile-onset Sporadic Amyotrophic Lateral Sclerosis with a Frameshift <i>FUS</i> Gene Mutation Presenting Unique Neuroradiological Findings and Cognitive Impairment

“…We herein report a case of juvenile-onset SALS with a frameshift FUS gene mutation presenting unique neuroradiological findings and cognitive impairment. A subset of juvenile-onset FALS/SALS cases of FUS gene mutations has been reported to have mental retardation or learning difficulty (6)(7)(8)(9)(10)(11). The present case further supports the association between FUS gene mutations and this particular phenotype.…”

“…Therefore, the FUS gene mutation in the proband might have occurred de novo, or a sporadic occurrence in this family might be due to incomplete penetrance of the disease. Several FUS gene mutations have been identified in juvenile-onset SALS cases, and some of them were genetically confirmed as de novo mutations (6,8,10,11,(17)(18)(19)(20). Typically, most juvenile-onset SALS cases associated with FUS gene mutations exhibit a rapid progression, with short disease duration, to death or tracheotomy (6).…”

Phosphorylation of C-terminal tyrosine 526 in FUS impairs its nuclear import

“…The NLS of FUS has been shown to bind to transportin (Guttinger et al, 2004;Lee et al, 2006), and knockdown of both transportin homologues, TNPO1 and transportin 2 (TNPO2), results in cytoplasmic localisation of FUS (Dormann et al, 2010). The P525L mutation causes one of the most severe forms of juvenile-onset ALS (Baumer et al, 2010;Huang et residue introduces a kink into the main chain, enabling hydrophobic interactions with the hydrophobic pocket of TNPO1, which engulfs the proline side chain and phenyl ring of Y526, enabling the formation of a hydrogen bond to occur between Y526 of FUS and D384 of TNPO1. Thus, the tyrosine residue at position 526 might play a central role in mediating the interaction between FUS and TNPO1.…”

Modeling ALS and FTLD proteinopathies in yeast: An efficient approach for studying protein aggregation and toxicity

“…[83][84][85] Similar observations were reported for FUS inclusions. 86,87 It is conceivable that pathological aggregates of TDP-43 and FUS might also share a common seeding mechanism of propagation with cell-to-cell transmission, which would explain the rapid progressive nature of ALS. 88 A pathogenic spreading mechanism was recently proposed for several major disease-linked protein aggregates, formed by Aβ, α-synuclein, Tau and polyglutamine.…”